TW202402292A - Belumosudil metabolites and uses thereof in the treatment of chronic graft-versus-host disease - Google Patents
Belumosudil metabolites and uses thereof in the treatment of chronic graft-versus-host disease Download PDFInfo
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Abstract
Description
本文涉及貝魯舒地爾(belumosudil)的代謝物及所述代謝物治療患者的自體免疫病症(包括用於治療慢性移植物抗宿主病(chronic graft-versus-host disease,cGVHD))的用途。This article relates to metabolites of belumosudil and the use of such metabolites to treat autoimmune disorders in patients, including for the treatment of chronic graft-versus-host disease (cGVHD). .
慢性移植物抗宿主病(cGVHD)是一種免疫介導的炎性和纖維化病症。它是實體器官移植和同種異體造血細胞移植(alloHCT)後潛在的嚴重併發症。cGVHD影響高達所有alloHCT接受者的70%,在兒童中的發病率為20%至50%。它是在alloHCT後2年以上發生非復發性死亡的主要原因。在美國,cGVHD的估計患病人數為14,000名患者(截至2016年)。(Bachier CR等人: Epidemiology and real-world treatment of chronic graft-versus-host disease post allogeneic hematopoietic cell transplantation: A US claims analysis.2019年12月7日至10日在佛羅里達州奧蘭多(Orlando, FL)舉行的ASH 2019上發表)(「Bachier等人」)。 Chronic graft-versus-host disease (cGVHD) is an immune-mediated inflammatory and fibrotic disorder. It is a potentially serious complication after solid organ transplantation and allogeneic hematopoietic cell transplantation (alloHCT). cGVHD affects up to 70% of all alloHCT recipients, with an incidence of 20% to 50% in children. It is the leading cause of non-recurrent death more than 2 years after alloHCT. The estimated prevalence of cGVHD in the United States is 14,000 patients (as of 2016). (Bachier CR et al.: Epidemiology and real-world treatment of chronic graft-versus-host disease post allogeneic hematopoietic cell transplantation: A US claims analysis. Held in Orlando, FL, December 7-10, 2019 Published at ASH 2019) ("Bachier et al.").
如通過Lee症狀量表(LSS)(它衡量cGVHD對患者的機能和健康的影響)所評估的,cGVHD患者的生活品質(QOL)嚴重受損。據報導,只有三分之一的患有cGVHD並開始系統治療的患者將到5年之前存活、處於緩解狀態並停止免疫抑制療法。(Lee SJ等人: Success of immunosuppressive treatments in patients with chronic graft-versus-host disease.Biol Blood Marrow Transpl 24:555-562, 2018)(「Lee等人」)。 The quality of life (QOL) of patients with cGVHD is severely impaired, as assessed by the Lee Symptom Scale (LSS), which measures the impact of cGVHD on a patient's functioning and health. It has been reported that only one-third of patients with cGVHD who initiate systemic therapy will be alive, in remission, and discontinue immunosuppressive therapy by 5 years. (Lee SJ et al.: Success of immunosuppressive treatments in patients with chronic graft-versus-host disease . Biol Blood Marrow Transpl 24:555-562, 2018) ("Lee et al.").
cGVHD的病理生理學可以分為三個階段:組織損傷所引起的早期炎症、適應性免疫系統失調、以及慢性炎症和伴隨纖維化的異常組織修復。The pathophysiology of cGVHD can be divided into three stages: early inflammation caused by tissue damage, dysregulation of the adaptive immune system, and chronic inflammation and abnormal tissue repair accompanied by fibrosis.
美國國立衛生研究院(NIH)定義的中度至重度慢性移植物抗宿主病(cGVHD)的一線療法是單獨的皮質類固醇或者皮質類固醇與西羅莫司(sirolimus)或鈣調磷酸酶抑制劑的組合。然而,高達70%的患者需要額外的療法線。(Bachier CR等人)。此外,長期使用皮質類固醇與顯著的副作用有關。(Lee等人)。First-line therapy for moderate-to-severe chronic graft-versus-host disease (cGVHD) as defined by the National Institutes of Health (NIH) is corticosteroids alone or corticosteroids with sirolimus or a calcineurin inhibitor combination. However, up to 70% of patients require additional lines of therapy. (Bachier CR et al.). Furthermore, long-term use of corticosteroids is associated with significant side effects. (Lee et al.).
cGVHD的管理隨著標靶治療的出現而不斷發展。cGVHD的特徵在於促炎細胞因子IL-21和IL-17的過量產生以及T濾泡輔助細胞和B細胞的過度活化,這又導致過度產生抗體。The management of cGVHD continues to evolve with the advent of targeted therapies. cGVHD is characterized by overproduction of the proinflammatory cytokines IL-21 and IL-17 and overactivation of T follicular helper cells and B cells, which in turn leads to overproduction of antibodies.
在2017年,美國食品和藥物管理局批准依魯替尼(ibrutinib,一種布魯頓氏酪胺酸激酶抑制劑)用於治療在一條或多條系統療法線失敗後的患cGVHD成人。在要求具有> 25%體表面積紅斑皮疹或NIH口腔得分> 4的cGVHD患者中,一項使用依魯替尼的研究報告了總反應率(ORR)為67%且因治療期間出現的不良事件(TEAE)所引起的停藥率為43%。(Waller EK等人: Ibrutinib for chronic graft-versus-host disease after failure of prior therapy: 1-Year update of a phase 1b/2 study.Biol Blood Marrow Transpl 25:2002-2007, 2019)。 In 2017, the U.S. Food and Drug Administration approved ibrutinib, a Bruton's tyrosine kinase inhibitor, for the treatment of adults with cGVHD after failure of one or more lines of systemic therapy. In patients with cGVHD requiring an erythematous rash >25% of body surface area or an NIH oral score >4, a study using ibrutinib reported an overall response rate (ORR) of 67% and was limited by treatment-emergent adverse events ( TEAE)-induced discontinuation rate was 43%. (Waller EK et al.: Ibrutinib for chronic graft-versus-host disease after failure of prior therapy: 1-Year update of a phase 1b/2 study . Biol Blood Marrow Transpl 25:2002-2007, 2019).
仍有機會針對患有cGVHD的患者(包括≥ 1種療法線失敗的患者)研究其他治療選項。There remain opportunities to investigate additional treatment options for patients with cGVHD, including those who have failed ≥1 line of therapy.
本文提供了貝魯舒地爾的代謝物以及所述代謝物治療患者的ROCK2介導的疾病(包括治療諸如cGVHD的自體免疫病症)的用途。在一個實施例中,本文包括化合物2-(3-(4-(1H-吲唑-5-基胺基)喹唑啉-e-基)苯氧基)乙醯胺治療自體免疫病症(在一些實施例中,治療cGVHD)的用途。Provided herein are metabolites of berusudil and the use of the metabolites to treat ROCK2-mediated diseases in patients, including the treatment of autoimmune disorders such as cGVHD. In one embodiment, the compound 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-e-yl)phenoxy)acetamide is included herein for the treatment of an autoimmune disorder ( In some embodiments, use to treat cGVHD).
本文進一步提供了呈分離形式的貝魯舒地爾代謝物或其醫藥上可接受的鹽,以及它們用於治療自體免疫病症(在一些實施例中,治療cGVHD)的用途。本文提供了一種分離的或合成的化合物或其醫藥上可接受的鹽,所述化合物包含貝魯舒地爾葡萄糖醛酸苷、O-脫烷基貝魯舒地爾硫酸鹽、單羥基貝魯舒地爾及/或貝魯舒地爾二醇。Further provided herein are berusuudil metabolites, or pharmaceutically acceptable salts thereof, in isolated forms, and their use for treating autoimmune disorders, in some embodiments, treating cGVHD. Provided herein is an isolated or synthetic compound or a pharmaceutically acceptable salt thereof, the compound comprising berusuudil glucuronide, O-dealkylated berusumidil sulfate, monohydroxyberusuudil Sudil and/or berusuldildiol.
本文進一步提供了貝魯舒地爾的代謝途徑,用於製備用於治療受試者的自體免疫性疾病的藥物。本文公開的貝魯舒地爾代謝物及/或貝魯舒地爾的代謝途徑的用途可用於準備用於治療受試者的自體免疫性疾病的方案。This article further provides a metabolic pathway of berusudil for use in preparing a medicament for treating an autoimmune disease in a subject. The use of the berusudil metabolites and/or the metabolic pathways of berusudil disclosed herein can be used to prepare regimens for treating autoimmune diseases in a subject.
透過參考旨在舉例說明非限制性實施例的詳細描述和實例可以更全面理解本發明實施例。Embodiments of the present invention may be understood more fully by reference to the detailed description and examples, which are intended to illustrate, non-limiting embodiments.
概述Overview
貝魯舒地爾是一種口服選擇性rho相關的含捲曲螺旋的蛋白激酶2(ROCK2)抑制劑。ROCK2抑制作用於失調的適應性免疫系統和由於異常組織修復而發生的纖維化。貝魯舒地爾分別以大約100 nM和3 µM的IC 50值抑制ROCK2和ROCK1。貝魯舒地爾在離體或體外人類T細胞測定中經由調節STAT3/STAT5磷酸化和改變Th17/Treg平衡來下調促發炎反應。在體外,貝魯舒地爾還抑制異常的促纖維化訊息傳遞。在體內,貝魯舒地爾在慢性GVHD的動物模型中展現出活性。 Begrusudil is an oral, selective Rho-associated coiled-coil-containing protein kinase 2 (ROCK2) inhibitor. ROCK2 inhibition acts on a dysregulated adaptive immune system and fibrosis that occurs due to abnormal tissue repair. Begrusudil inhibits ROCK2 and ROCK1 with IC50 values of approximately 100 nM and 3 µM, respectively. Berusuudil downregulates pro-inflammatory responses in ex vivo or in vitro human T cell assays by modulating STAT3/STAT5 phosphorylation and altering Th17/Treg balance. In vitro, berusudil also inhibits abnormal profibrotic signaling. In vivo, berusudil exhibits activity in animal models of chronic GVHD.
化合物貝魯舒地爾的化學名稱如下:2-{3-[4-(1 H-吲唑-5-基胺基)-2-喹唑啉基]苯氧基}- N-(丙-2-基)乙醯胺。化合物貝魯舒地爾也稱為KD025。貝魯舒地爾的甲磺酸鹽在美國和其他國家作為REZUROCK TM銷售,用於治療患有慢性GVHD(cGVHD)的患者,在一些情況下,用於治療在至少兩條先前系統療法線失敗後的慢性GVHD患者。REZUROCK TM的活性藥物成分是貝魯舒地爾甲磺酸鹽,其分子式為C 27H 28N 6O 5S,分子量為548.62 g/mol,並且化學名稱為2-{3-[4-(1 H-吲唑-5-基胺基)-2-喹唑啉基]苯氧基}- N-(丙-2-基)乙醯胺甲磺酸鹽(1 : 1)。 The chemical name of the compound berusudil is as follows: 2-{3-[4-(1 H -indazol-5-ylamine)-2-quinazolinyl]phenoxy}- N -(propan- 2-yl)acetamide. The compound berusudil is also known as KD025. Berusudil mesylate is marketed in the United States and other countries as REZUROCK TM for the treatment of patients with chronic GVHD (cGVHD) who, in some cases, have failed at least two prior lines of systemic therapy patients with chronic GVHD. The active pharmaceutical ingredient of REZUROCK TM is berusudil mesylate, whose molecular formula is C 27 H 28 N 6 O 5 S, molecular weight is 548.62 g/mol, and chemical name is 2-{3-[4-( 1H -indazol-5-ylamine)-2-quinazolinyl]phenoxy} -N- (propan-2-yl)acetamide methanesulfonate (1:1).
貝魯舒地爾甲磺酸鹽的化學結構如下: The chemical structure of berusudil mesylate is as follows:
如實例1的研究中使用的放射性標記的貝魯舒地爾的化學結構具有以下結構: 。 The chemical structure of radiolabeled berusudil as used in the study of Example 1 has the following structure: .
貝魯舒地爾和用於製備所述化合物的過程描述於以下美國專利:美國專利號8,357,693、美國專利號9,815,820、美國專利號10,183,931和美國專利號10,696,660。Berusuudil and processes used to prepare the compounds are described in the following US patents: US Patent No. 8,357,693, US Patent No. 9,815,820, US Patent No. 10,183,931, and US Patent No. 10,696,660.
透過控制ROCK2活性,貝魯舒地爾介導免疫細胞功能和纖維化途徑中的訊息傳遞,從而減輕由這種衰竭性疾病造成的影響,諸如多種組織的炎症以及可能涉及包括肺、肝膽系統、肌肉骨骼系統、胃腸(GI)道和皮膚在內的多個器官的纖維化變化。By controlling ROCK2 activity, berusudil mediates immune cell function and signaling in fibrotic pathways, thereby mitigating the effects of this debilitating disease, such as inflammation in multiple tissues and potentially involving the lungs, hepatobiliary system, Fibrotic changes in multiple organs including the musculoskeletal system, gastrointestinal (GI) tract, and skin.
體外評估已經表明,貝魯舒地爾的代謝主要依賴於細胞色素P450 CYP3A4的活性,並且貝魯舒地爾的溶解度是pH依賴性的。小鼠、大鼠、兔和狗中的臨床前研究已經表明,貝魯舒地爾經歷肝臟代謝形成2種主要代謝物,稱為KD025m1(次要代謝物)和KD025m2(主要代謝物)。In vitro evaluations have shown that the metabolism of berusudil is primarily dependent on the activity of the cytochrome P450 CYP3A4 and that the solubility of berusudil is pH-dependent. Preclinical studies in mice, rats, rabbits and dogs have shown that berusudil undergoes hepatic metabolism to form 2 major metabolites, termed KD025m1 (minor metabolite) and KD025m2 (major metabolite).
KD025m1的化學名稱為2-(3-(4-(1H-吲唑-5-基胺基)喹唑啉-2-基)苯氧基)乙醯胺,並且具有以下結構: 。 The chemical name of KD025m1 is 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetamide and has the following structure: .
KD025m2的化學名稱為2-(3-(4-(1H-吲唑-5-基胺基)喹唑啉-2-基)苯氧基)乙酸,並且具有以下結構: 。 The chemical name of KD025m2 is 2-(3-(4-(1H-indazol-5-yllamino)quinazolin-2-yl)phenoxy)acetic acid and has the following structure: .
將KD025m1和KD025m2在貝魯舒地爾開發專案的臨床試驗中量化;主要代謝物KD025m2的暴露值為母本的15%至20%,而次要的更具活性的代謝物KD025m1的暴露值為母本的< 5%。KD025m1 and KD025m2 were quantified in clinical trials in the berusudil development program; exposure to the major metabolite KD025m2 was 15% to 20% of parent, while exposure to the minor, more active metabolite KD025m1 was <5% of the maternal parent.
使用放射性標記的化合物的人體質量平衡研究對於理解研究或臨床藥物的藥物動力學(PK)特性非常重要。進行質量平衡研究以鑒定和量化代謝物並且確定消除途徑的特徵。用於確定絕對生物利用度的一種方法是使用微追蹤劑量。Human mass balance studies using radiolabeled compounds are important for understanding the pharmacokinetic (PK) properties of investigational or clinical drugs. Mass balance studies were performed to identify and quantify metabolites and characterize elimination pathways. One method used to determine absolute bioavailability is the use of microtrace doses.
瞭解研究藥物或臨床藥物的代謝途徑對於確定分子(包括經由代謝途徑消耗的和產生的能量以及合成的分子和產生的副產物)對患者的影響非常重要。瞭解代謝途徑對於提供關於參與催化生物學機制的酶的資訊也有用。因此,除此之外,代謝途徑可能被證明在確定藥物-藥物相互作用(DDI)、開發劑量修飾及/或解決藥物投予的潛在副作用方面尤其有用。參見例如,Schueller, O., 等人 , 「 A Phase I Pharmacokinetic Drug Interaction Study of Belumosudil Coadministered With CYP3A4 Inhibitors and Inducers and Proton Pump Inhibitors,」 Clinical Pharmacology in Drug Development, 2022, 11(7) 795-806(在評估藥物-藥物相互作用中使用代謝物暴露)。 Understanding the metabolic pathways of investigational or clinical drugs is important in determining the effects of molecules on patients, including the energy consumed and produced via metabolic pathways and the molecules synthesized and by-products produced. Understanding metabolic pathways is also useful in providing information about enzymes involved in catalyzing biological mechanisms. Thus, among other things, metabolic pathways may prove particularly useful in identifying drug-drug interactions (DDIs), developing dose modifications, and/or addressing potential side effects of drug administration. See, e.g., Schueller, O., et al. , “ A Phase I Pharmacokinetic Drug Interaction Study of Belumosudil Coadministered With CYP3A4 Inhibitors and Inducers and Proton Pump Inhibitors ,” Clinical Pharmacology in Drug Development, 2022, 11(7) 795-806 (in Use metabolite exposure in the assessment of drug-drug interactions).
本文提供了貝魯舒地爾的代謝途徑。鑒定了先前未知的代謝物,包括O-脫烷基貝魯舒地爾硫酸鹽和貝魯舒地爾葡萄糖醛酸苷代謝物(在血漿中鑒定)和單羥基貝魯舒地爾與貝魯舒地爾二醇代謝物(在糞便中鑒定)。這些化合物也可用於治療ROCK2介導的疾病(包括cGVHD)及/或用於開發包括用於cGVHD的治療在內的治療方法,例如像確定DDI、劑量修飾和解決副作用。 定義 This article provides the metabolic pathways of berusudil. Previously unknown metabolites were identified, including O-dealkylated berusudil sulfate and berusudil glucuronide metabolites (identified in plasma) and monohydroxyberusudil and berusudil Sudildiol metabolites (identified in feces). These compounds may also be useful in the treatment of ROCK2-mediated diseases (including cGVHD) and/or in the development of therapeutics including treatments for cGVHD, such as determining DDI, dose modification and addressing side effects. definition
如本文所用的「約」」包括由術語約修飾的確切量以及預期在實驗誤差內(諸如在15%、10%或5%內)的量。例如,「約200 mg」意指「200 mg」以及在實驗誤差(例如,200 mg的正或負15%、10%或5%)內的mg範圍。如本文所用,術語「約」可用於修飾範圍以及還有特定值。"About" as used herein includes the exact amounts modified by the term about as well as amounts expected to be within experimental error (such as within 15%, 10%, or 5%). For example, "about 200 mg" means "200 mg" and a range of mg within experimental error (eg, plus or minus 15%, 10%, or 5% of 200 mg). As used herein, the term "about" may be used to modify a range as well as a specific value.
「API」意指「活性藥物成分」。"API" means "active pharmaceutical ingredient".
「同種異體造血幹細胞移植(allo-HSCT)」(也稱為骨髓移植或幹細胞移植)或者「同種異體造血細胞移植(allo-HCT)」,其是指將來自捐贈者的造血細胞移植到不是同卵雙胞胎的接受者中的程序。用於同種異體移植的造血幹細胞來源可以是周邊血液幹細胞(PBSC)或骨髓(BM)。在一些情況下,可使用臍帶血。捐贈者和接受者的人類白血球抗原(HLA)基因可能匹配,諸如兄弟姐妹。捐贈者和接受者可能是僅半匹配(單倍體相合)的父母和孩子。"Allogeneic hematopoietic stem cell transplantation (allo-HSCT)" (also called bone marrow transplant or stem cell transplant) or "allogeneic hematopoietic cell transplantation (allo-HCT)" refers to the transplantation of hematopoietic cells from a donor into a person who is not the same Procedure in recipients of zygotic twins. The source of hematopoietic stem cells for allogeneic transplantation can be peripheral blood stem cells (PBSC) or bone marrow (BM). In some cases, umbilical cord blood may be used. The donor and recipient may have human leukocyte antigen (HLA) genetic matches, such as siblings. The donor and recipient may be only half-matched (haploidentical) parents and children.
當本文使用術語「貝魯舒地爾」時,應當理解,除非上下文另有明確指示,否則該術語可涵蓋任何形式的化合物貝魯舒地爾以及其醫藥上可接受的鹽。術語「貝魯舒地爾」既指化合物貝魯舒地爾(例如,游離鹼形式、無定形形式或結晶形式),亦指貝魯舒地爾的醫藥上可接受的鹽(例如,如在REZUROCK TM中使用的甲磺酸鹽形式),又指可在調配物或醫藥組成物中使用以用於將化合物投予至患者的貝魯舒地爾的任何形式。 When the term "berusudil" is used herein, it is to be understood that the term may encompass any form of the compound berusudil as well as pharmaceutically acceptable salts thereof, unless the context clearly indicates otherwise. The term "begrusudil" refers to both the compound begrusudil (e.g., the free base form, the amorphous form, or the crystalline form) and a pharmaceutically acceptable salt of berusudil (e.g., as in mesylate form as used in REZUROCK ™ ), also refers to any form of berusudil that can be used in a formulation or pharmaceutical composition for administering the compound to a patient.
「臨床終點」或「研究終點」是指臨床試驗中的事件或結果,所述事件或結果可以客觀地測量以確定如在臨床試驗中設計的藥物或投予方案的結果和潛在有益效果。臨床終點的例子包括以下。總反應率(ORR)是研究或治療組中在某段時間內對治療具有部分反應(PR)或完全反應(CR)的人的百分比。無失敗存活期(FFS)是指從第一劑量的貝魯舒地爾到失敗事件的時間,或者貝魯舒地爾的開始與新cGVHD療法的添加、基礎疾病的復發或非復發性死亡(NRM)之間的間隔。總存活期(OS)意指從疾病的診斷日期或治療開始起的時間長度。反應持續時間(DOR)意指從初始反應時間(例如,PR或CR)直到記錄的從cGVHD的最佳反應進展的時間、從初始反應到開始額外的系統cGVHD療法或死亡的時間。到下一治療的時間(TTNT)意指到開始後續系統cGVHD療法的時間。A "clinical endpoint" or "study endpoint" refers to an event or outcome in a clinical trial that can be objectively measured to determine the outcome and potential beneficial effects of a drug or administration regimen as designed in a clinical trial. Examples of clinical endpoints include the following. Overall response rate (ORR) is the percentage of people in a study or treatment group who have a partial response (PR) or complete response (CR) to treatment over a certain period of time. Failure-free survival (FFS) is defined as the time from the first dose of berusudil to the event of failure, or the initiation of berusudil versus the addition of a new cGVHD therapy, recurrence of underlying disease, or non-relapse death ( NRM). Overall survival (OS) refers to the length of time from the date of diagnosis of disease or initiation of treatment. Duration of response (DOR) means the time from initial response (eg, PR or CR) until documented progression of optimal response from cGVHD, time from initial response to initiation of additional systemic cGVHD therapy, or death. Time to next treatment (TTNT) means the time to start subsequent systemic cGVHD therapy.
「臨床推薦量」或「臨床推薦劑量」是指藥物化學領域的通常知識者在臨床試驗後推薦及/或批准投予至患者以治療所討論的疾病狀態的API的量或劑量,例如如本文實例1和2中所述。"Clinically recommended amount" or "clinically recommended dose" means an amount or dosage of an API that a person of ordinary skill in the field of medicinal chemistry recommends and/or approves for administration to patients following clinical trials to treat the disease state in question, e.g., as herein As described in Examples 1 and 2.
「CYP3A」是指p-450同工酶的CYP3A家族,包括CYP3A4。“CYP3A” refers to the CYP3A family of p-450 isoenzymes, including CYP3A4.
「病症」和「疾病」在本文中可互換且同義地使用,在任一術語的完整範圍內包括需要治療的受試者的任何病症。"Condition" and "disease" are used interchangeably and synonymously herein and include to the full scope of either term any condition in a subject in need of treatment.
「葡萄糖醛酸苷」也稱為葡糖醛苷,是透過將葡糖醛酸與另一種物質經由糖苷鍵連接產生的任何物質。葡萄糖醛酸苷屬於糖苷類。"Glucuronide", also known as glucuronide, is any substance produced by linking glucuronic acid to another substance through a glycosidic bond. Glucuronides belong to the class of glycosides.
「葡萄糖醛酸化」是指化合物轉化為葡萄糖醛酸苷。它是動物用來幫助排泄無法用作能源的有毒物質、藥物或其他物質的方法。葡萄糖醛酸化涉及母本化合物由UDP-葡萄糖醛酸基轉移酶(UGT)代謝為在沒有外排轉運蛋白的幫助下無法從細胞排出的親水且帶負電荷的葡萄糖醛酸苷。透過兩種驅動力控制了代謝活性細胞中母本化合物經由葡萄糖醛酸化的消除:透過UGT酶的葡萄糖醛酸苷的形成,以及這些葡萄糖醛酸苷透過位於各種藥物處置器官中的細胞表面上的外排轉運蛋白的(極性)排泄。"Glucuronidation" refers to the conversion of a compound into a glucuronide. It is a method used by animals to help eliminate toxic substances, drugs, or other substances that cannot be used as energy sources. Glucuronidation involves metabolism of the parent compound by UDP-glucuronosyltransferases (UGTs) to hydrophilic and negatively charged glucuronides that cannot be excreted from the cell without the aid of efflux transporters. The elimination of parent compounds by glucuronidation in metabolically active cells is controlled by two driving forces: the formation of glucuronides by UGT enzymes, and the passage of these glucuronides on the cell surface located in various drug-processing organs. (Polar) excretion of efflux transporters.
「免疫抑制療法」(IST)是指通常在allo-HSCT後投予至少六個月以試圖預防GVHD的療法。IST的例子包括西羅莫司、強體松(prednisone)和鈣調磷酸酶抑制劑(諸如他克莫司(tacrolimus)和環孢素)。"Immunosuppressive therapy" (IST) refers to therapy usually given for at least six months after allo-HSCT in an attempt to prevent GVHD. Examples of ISTs include sirolimus, prednisone, and calcineurin inhibitors such as tacrolimus and cyclosporine.
如本文所用的「分離的」與「基本上分離的」同義。如本文所用的「基本上分離的」意指所述化合物已經與體內環境分離,在所述體內環境中經由代謝途徑形成所述化合物。例如,當透過人的代謝途徑形成化合物時,當所述化合物不再包含在人體的器官或系統內而是被消除、離體排泄及/或以其他方式從體內去除(例如,經由抽取含有所述化合物的血液樣品)時,所述化合物是「分離的」。「基本上分離的」包括與代謝途徑的組分部分分離和基本上分離。例如,部分分離可以包括富含本文公開的一種或多種化合物的組成物或物質,例如,含有按重量計至少約5%,以及在一些實施例中,約10%或至少約15%代謝物。「基本上分離」可以包括含有按重量計至少約50%、至少約60%、至少約70%、至少約80%、至少約90%、至少約95%、至少約97%、或至少約99%代謝物的組成物。As used herein, "separate" is synonymous with "substantially separate." "Substantially isolated" as used herein means that the compound has been separated from the in vivo environment in which it was formed via metabolic pathways. For example, when a compound is formed through a person's metabolic pathways, when the compound is no longer contained within the body's organs or systems but is eliminated, excreted, and/or otherwise removed from the body (e.g., via extraction of the compound containing the When a blood sample of said compound is provided), said compound is "isolated". "Substantially separated" includes partially separated and substantially separated from components of a metabolic pathway. For example, a partial isolation may include a composition or material enriched in one or more compounds disclosed herein, e.g., containing at least about 5%, and in some embodiments, about 10% or at least about 15% metabolites by weight. "Substantially separated" may include containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight. % metabolite composition.
Lee症狀量表(LSS)總分衡量對患者機能和健康的影響。Lee症狀量表是一種為測量cGVHD的症狀而開發的30項量表,並且描述於Lee SJ等人, Development and validation of a scale to measure symptoms of chronic graft-versus host disease.Biol Blood Marrow Transplant 2002; 8:444-452。 The Lee Symptom Scale (LSS) total score measures the impact on patient functioning and health. The Lee Symptom Scale is a 30-item scale developed to measure symptoms of cGVHD and is described in Lee SJ et al., Development and validation of a scale to measure symptoms of chronic graft-versus host disease . Biol Blood Marrow Transplant 2002; 8:444-452.
「治療線(Line of treatment)」或「療法線(line of therapy)」描述了隨著患者疾病的進展向患者給予不同療法的順序或次序。初始治療(一線療法)可能不起作用或可能在一段時間後停止起作用。在中止一線療法後,可給予第二種不同的治療(二線療法)。當二線療法不起作用或停止起作用時,可給予後續線療法。一些患者可能會在病程中被投予多線療法。A "line of treatment" or "line of therapy" describes the order or sequence in which different therapies are given to a patient as the patient's disease progresses. Initial treatment (first-line therapy) may not work or may stop working after a while. After discontinuation of first-line therapy, a second, different treatment may be given (second-line therapy). Subsequent lines of therapy may be given when second-line therapy does not work or stops working. Some patients may be given multiple lines of therapy over the course of the disease.
美國國立衛生研究院(NIH)定義的中度至重度慢性移植物抗宿主病(cGVHD)的一線療法可以是單獨的皮質類固醇或者皮質類固醇與西羅莫司或鈣調磷酸酶抑制劑的組合。(Carpenter PA等人: A phase II/III randomized, multicenter trial of prednisone/sirolimus versus prednisone/sirolimus/calcineurin inhibitor for the treatment of chronic graft-versus-host disease: BMT CTN 0801.Haematologica 103:1915-1924, 2018)。 First-line therapy for moderate-to-severe chronic graft-versus-host disease (cGVHD), as defined by the National Institutes of Health (NIH), can be corticosteroids alone or in combination with sirolimus or a calcineurin inhibitor. (Carpenter PA et al.: A phase II/III randomized, multicenter trial of prednisone/sirolimus versus prednisone/sirolimus/calcineurin inhibitor for the treatment of chronic graft-versus-host disease : BMT CTN 0801. Haematologica 103:1915-1924, 2018 ).
用於治療cGVHD的皮質類固醇療法的例子包括但不限於強體松、腎上腺皮質酮(prednisolone)、甲基腎上腺皮質酮和布地奈德(budesonide)。用於治療cGVHD的先前系統療法的例子包括但不限於強體松、他克莫司(tacrolimus)、體外光照治療(extracorporeal photopheresis,ECP)、西羅莫司、依魯替尼(ibruitinib)、盧梭替尼(ruxolitinib)、嗎替麥考酚酯(mycophenolate mofetil,MMF)、利妥昔單抗(rituximab)、胺甲喋呤(methotrexate MTX)、環孢素、伊馬替尼(imatinib)、伊沙佐米(ixazomib)和奧法木單抗(ofatumumab)。Examples of corticosteroid therapies used to treat cGVHD include, but are not limited to, prednisone, prednisolone, methyladrenocorticosterone, and budesonide. Examples of prior systemic therapies used to treat cGVHD include, but are not limited to, prednisone, tacrolimus, extracorporeal photopheresis (ECP), sirolimus, ibruitinib, Rousseau ruxolitinib, mycophenolate mofetil (MMF), rituximab, methotrexate MTX, cyclosporine, imatinib, ISA ixazomib and ofatumumab.
「代謝途徑」是指將一種化學物質轉化(轉變)為另一種化學物質的生物化學反應,如合成代謝途徑或分解代謝途徑。合成代謝途徑涉及從較小的分子構建較大的分子,這是需要能量的過程。分解代謝途徑涉及較大的分子的分解,通常釋放能量。"Metabolic pathway" refers to the biochemical reaction that converts (converts) one chemical substance into another chemical substance, such as an anabolic pathway or a catabolic pathway. Anabolic pathways involve building larger molecules from smaller molecules, a process that requires energy. Catabolic pathways involve the breakdown of larger molecules, often releasing energy.
「代謝物」是指在代謝途徑期間產生的中間體或產物,包括經由合成代謝途徑(較大的分子經由分解代謝途徑(較小的分子或部分)產生的那些。"Metabolite" means an intermediate or product produced during a metabolic pathway, including those produced via the anabolic pathway (larger molecules) via the catabolic pathway (smaller molecules or parts).
「骨髓盡除式移植(Myeloablative transplant)」是指在移植自體或同種異體造血幹細胞之前使用非常高劑量的化療或放射的移植過程。非骨髓盡除式移植或降低強度移植涉及患者在移植同種異體造血幹細胞之前進行較低強度的化療。"Myeloablative transplant" refers to a transplantation process that uses very high doses of chemotherapy or radiation before transplanting autologous or allogeneic hematopoietic stem cells. Non-medullary transplantation or reduced-intensity transplantation involves patients undergoing less intensive chemotherapy before transplantation of allogeneic hematopoietic stem cells.
「NIH肺部症狀得分」或「NIH cGVHD肺部得分」是基於臨床症狀的得分,範圍為0至3。0分用於無症狀,1分用於上樓梯時出現呼吸短促的症狀,2分用於平地時出現呼吸短促的症狀,以及3分用於休息時出現呼吸短促或需要氧氣。The "NIH Pulmonary Symptom Score" or "NIH cGVHD Pulmonary Score" is a score based on clinical symptoms and ranges from 0 to 3. A score of 0 is for no symptoms, a score of 1 is for symptoms of shortness of breath when climbing stairs, and a score of 2 is Use for symptoms of shortness of breath when on level ground, and 3 points for symptoms of shortness of breath or need for oxygen when resting.
除非上下文另有要求,否則「或」以包括性含義使用(等同於「及/或」)。Unless the context otherwise requires, "or" is used inclusively (equivalent to "and/or").
如本文所用的「患者」或「受試者」包括動物或人類,在一個實施例中包括人類。"Patient" or "subject" as used herein includes animals or humans, including humans in one embodiment.
「醫藥組成物」意指適於向個體投予的物質(其包括藥劑)的混合物。例如,醫藥組成物可包含無菌水溶液或以口服劑型(如錠劑或膠囊)配製的API。"Pharmaceutical composition" means a mixture of substances, including pharmaceutical agents, suitable for administration to an individual. For example, a pharmaceutical composition may include a sterile aqueous solution or an API formulated in an oral dosage form such as a tablet or capsule.
「醫藥上可接受的鹽」意指本文提供的化合物的生理上和醫藥上可接受的鹽。「醫藥上可接受的鹽」是指所公開的化合物的衍生物,其中藉由將現有的酸或鹼部分轉化為其鹽形式而對母本化合物進行修飾。醫藥上可接受的鹽的例子包括但不限於諸如胺等鹼性殘基的礦物酸鹽或有機酸鹽;諸如羧酸等酸性殘基的鹼鹽或有機鹽等。本發明的醫藥上可接受的鹽包括例如從無毒的無機酸或有機酸形成的母本化合物的常規無毒鹽。本發明的醫藥上可接受的鹽可以透過常規化學方法由含有鹼性或酸性部分的母本化合物合成。通常,此類鹽可以通過使這些化合物的游離酸或鹼形式與化學計量的適當鹼或酸在水中或在有機溶劑中或在水與有機溶劑的混合物中反應來製備;通常,像醚、乙酸乙酯、乙醇、異丙醇或乙腈的非水性介質是優選的。"Pharmaceutically acceptable salts" means physiologically and pharmaceutically acceptable salts of the compounds provided herein. "Pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds in which the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids, and the like. Pharmaceutically acceptable salts of the present invention include, for example, conventional nontoxic salts of the parent compound formed from nontoxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from the parent compound containing a basic or acidic moiety. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of water and organic solvents; typically, like ethers, acetic acid Non-aqueous media of ethyl ester, ethanol, isopropanol or acetonitrile are preferred.
如本文所用的「方案」是指用於將一種或多種API投予至需要治療的受試者的方法或計畫。術語「方案」旨在涵蓋患者的整體詳細護理計畫以及作為整體計畫一部分的單獨或部分步驟。例如,方案可包括用於患者將(或正在)接受的每種API的劑量、患者接受的API的組合、每種API的投予時間安排和方法(例如,考慮DDI、食物效應和不同調配物或遞送方式可能對吸收和生物利用度產生的影響)和副作用的管理,以及涵蓋一起考慮的劑量、組合、投予時間安排和方法以及副作用的總體計畫。"Regimen" as used herein refers to a method or plan for administering one or more APIs to a subject in need of treatment. The term "plan" is intended to cover the overall detailed plan of care for a patient and the individual or partial steps that are part of the overall plan. For example, a protocol may include doses for each API that the patient will (or is) receiving, combinations of APIs that the patient will receive, schedules and methods of administration for each API (e.g., taking into account DDI, food effects, and different formulations or the effect that the mode of delivery may have on absorption and bioavailability) and management of side effects, as well as an overall plan covering dosage, combinations, timing and methods of administration, and side effects considered together.
「副作用」意指可歸因於治療的除了所希望的效果以外的生理反應。在某些實施例中,副作用包括而不限於肝功能檢查異常、腎功能異常、肝毒性、腎毒性和肌病。可以直接或間接地檢測副作用。例如,血清中升高的轉胺酶水平可能指出肝毒性或肝功能異常。作為另一個例子,升高的膽紅素可能指出肝毒性或肝功能異常。"Side effect" means a physiological response other than the desired effect attributable to treatment. In certain embodiments, side effects include, but are not limited to, abnormal liver function tests, abnormal renal function, hepatotoxicity, nephrotoxicity, and myopathy. Side effects can be detected directly or indirectly. For example, elevated transaminase levels in serum may indicate hepatotoxicity or abnormal liver function. As another example, elevated bilirubin may indicate hepatotoxicity or abnormal liver function.
「類固醇難治性」(SR)cGVHD被定義為在使用類固醇或皮質類固醇時(在一個實施例中,在使用強體松時)cGVHD進展。"Steroid-refractory" (SR) cGVHD is defined as cGVHD progression while on steroids or corticosteroids (in one embodiment, on prednisone).
API的「治療有效量」意指在投予至人類以治療疾病(例如,cGVHD)時足以實現對所治療疾病狀態的治療的量。如應用於人的cGVHD,「治療(treating)」或「治療(treatment)」包括 (1) 降低發生cGVHD的風險及/或抑制cGVHD,即阻止或減少cGVHD或其臨床症狀的發展;(2) 緩解cGVHD,即引起cGVHD的消退、逆轉或改善或者減少其臨床症狀的數量、頻率、持續時間或嚴重程度。A "therapeutically effective amount" of an API means an amount sufficient to effect treatment of the disease state being treated when administered to a human to treat a disease (eg, cGVHD). As applied to cGVHD in humans, "treating" or "treatment" includes (1) reducing the risk of developing cGVHD and/or inhibiting cGVHD, that is, preventing or reducing the development of cGVHD or its clinical symptoms; (2) Relieve cGVHD, that is, cause the regression, reversal or improvement of cGVHD or reduce the number, frequency, duration or severity of its clinical symptoms.
API的治療有效量可能會根據待治療受試者的健康和身體狀況、疾病進展的程度、醫療狀況的評估和其他相關因素而有所不同。預期治療有效量可落入可以藉由試驗以及藉由參考例如如本文的實例1和2中以及科學文獻中所述的臨床試驗資料和結果確定的範圍內。 示例性實施例 The therapeutically effective amount of an API may vary depending on the health and physical condition of the subject to be treated, the extent of disease progression, assessment of the medical condition and other relevant factors. It is expected that a therapeutically effective amount may fall within a range that can be determined experimentally and by reference to clinical trial data and results, for example, as described in Examples 1 and 2 herein and in the scientific literature. Exemplary embodiments
本公開文本提供了貝魯舒地爾的代謝物及/或貝魯舒地爾代謝途徑。This disclosure provides metabolites of berusudil and/or berusudil metabolic pathways.
在一些實施例中,本文提供了一種分離的或合成的化合物或其醫藥上可接受的鹽,所述化合物包含貝魯舒地爾葡萄糖醛酸苷、O-脫烷基貝魯舒地爾硫酸鹽、單羥基貝魯舒地爾及/或貝魯舒地爾二醇。In some embodiments, provided herein is an isolated or synthetic compound, or a pharmaceutically acceptable salt thereof, comprising berusudil glucuronide, O-dealkylated berusudil sulfate salt, monohydroxyberusudil and/or berusudildiol.
本文提供的化合物和代謝途徑可用於治療患者的ROCK2介導的疾病,包括在自體免疫病症(如慢性GVHD(cGVHD))的治療中及/或在用於治療ROCK2介導的疾病的一種或多種治療及/或方案的開發中。The compounds and metabolic pathways provided herein may be used to treat ROCK2-mediated diseases in patients, including in the treatment of autoimmune disorders, such as chronic GVHD (cGVHD) and/or in one or more therapies for the treatment of ROCK2-mediated diseases. Multiple treatments and/or options are in development.
在一個實施例中,本文包括化合物2-(3-(4-(1H-吲唑-5-基胺基)喹唑啉-e-基)苯氧基)乙醯胺治療自體免疫病症(在一些實施例中,治療cGVHD)的用途。In one embodiment, the compound 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-e-yl)phenoxy)acetamide is included herein for the treatment of an autoimmune disorder ( In some embodiments, use to treat cGVHD).
在一些實施例中,本文提供了一種包含2-(3-(4-(1H-吲唑-5-基胺基)喹唑啉-e-基)苯氧基)乙醯胺的化合物,其用於治療受試者的自體免疫病症,其中所述自體免疫病症是cGVHD、急性GVHD(aGVHD)、肺纖維化、特發性肺纖維化、中度至重度乾癬、類風濕性關節炎、多發性硬化症、全身性紅斑狼瘡(SLE)、克隆氏症、異位性皮膚炎或濕疹。In some embodiments, provided herein is a compound comprising 2-(3-(4-(1H-indazol-5-yllamino)quinazolin-e-yl)phenoxy)acetamide, which For treating an autoimmune disorder in a subject, wherein the autoimmune disorder is cGVHD, acute GVHD (aGVHD), pulmonary fibrosis, idiopathic pulmonary fibrosis, moderate to severe psoriasis, rheumatoid arthritis , multiple sclerosis, systemic lupus erythematosus (SLE), Crohn's disease, atopic dermatitis or eczema.
在一些實施例中,本文提供了貝魯舒地爾的代謝物及/或貝魯舒地爾代謝途徑,其用於製備用於治療受試者的自體免疫性疾病的藥物;在一些實施例中,用於準備用於治療受試者的自體免疫性疾病的方案。In some embodiments, this article provides metabolites of berusudil and/or berusudil metabolic pathways, which are used to prepare medicaments for treating autoimmune diseases in a subject; in some embodiments In one example, to prepare a regimen for treating an autoimmune disease in a subject.
在一些實施例中,本文提供了貝魯舒地爾的代謝物及/或貝魯舒地爾代謝途徑,用於準備如下方案,所述方案包括開發單位劑量(例如,臨床推薦的單位劑量),用於向受試者投予活性藥劑;及/或包括待向所述受試者投予的活性藥劑的組合(例如,考慮到藥物-藥物相互作用);及/或考慮向受試者投予一種或多種活性藥劑的時間安排;及/或用於避免或最小化由向受試者治療性使用至少一種活性藥劑所引起的一種或多種副作用。In some embodiments, the metabolites of berusudil and/or the metabolic pathways of berusuudil are provided herein for use in preparing a regimen that includes developing a unit dose (e.g., a clinically recommended unit dose) , for administering an active agent to a subject; and/or including a combination of active agents to be administered to the subject (e.g., taking into account drug-drug interactions); and/or considering administering to the subject The timing of administration of one or more active agents; and/or to avoid or minimize one or more side effects resulting from the therapeutic use of at least one active agent to a subject.
在一些實施例中,本文提供了具有下式的化合物: ; ; ; ;或 其中 表示將所述分子括弧部分內的任何可用碳原子與相鄰所述括弧的一個或多個部分連接的單鍵;或其醫藥上可接受的鹽。 In some embodiments, provided herein are compounds of the formula: ; ; ; ;or in means a single bond connecting any available carbon atom within a bracketed portion of the molecule to one or more adjacent portions of the bracket; or a pharmaceutically acceptable salt thereof.
在一些實施例中,本文提供了一種分離的化合物,其為具有下式的貝魯舒地爾葡萄糖醛酸苷: , 或其醫藥上可接受的鹽;在一些實施例中,其中所述貝魯舒地爾葡萄糖醛酸苷的分子量為628。 In some embodiments, provided herein is an isolated compound that is berusuudil glucuronide having the formula: , or a pharmaceutically acceptable salt thereof; in some embodiments, the molecular weight of berusudil glucuronide is 628.
在一些實施例中,本文提供了一種分離的化合物,其為具有下式的O-脫烷基貝魯舒地爾硫酸鹽: , 或其醫藥上可接受的鹽;在一些實施例中,其中所述O-脫烷基貝魯舒地爾硫酸鹽的分子量為433。 In some embodiments, provided herein is an isolated compound that is O-dealkylated berusudil sulfate having the formula: , or a pharmaceutically acceptable salt thereof; in some embodiments, the molecular weight of the O-dealkylated berusudil sulfate is 433.
在一些實施例中,本文提供了一種分離的化合物,其為具有下式的單羥基貝魯舒地爾: ;或 或其醫藥上可接受的鹽;在一些實施例中,其中所述單羥基貝魯舒地爾的分子量為468。 In some embodiments, provided herein is an isolated compound that is monohydroxyberusudil having the formula: ;or Or a pharmaceutically acceptable salt thereof; in some embodiments, wherein the molecular weight of monohydroxyberusudil is 468.
在一些實施例中,本文提供了一種分離的化合物,其為具有下式的貝魯舒地爾二醇: , 或其醫藥上可接受的鹽;在一些實施例中,其中所述貝魯舒地爾二醇的分子量為486。 In some embodiments, provided herein is an isolated compound that is berusudildiol having the formula: , or a pharmaceutically acceptable salt thereof; in some embodiments, the molecular weight of berusudildiol is 486.
在一些實施例中,本文提供了一種包含任一種或多種前述化合物的醫藥組成物,或所述醫藥組成物治療受試者的自體免疫病症的用途,其中所述自體免疫病症是慢性GVHD(cGVHD)、急性GVHD(aGVHD)、肺纖維化、特發性肺纖維化、中度至重度乾癬、類風濕性關節炎、多發性硬化症、全身性紅斑狼瘡(systemic lupus erythematosus,SLE)、克隆氏症、異位性皮膚炎或濕疹。In some embodiments, provided herein is a pharmaceutical composition comprising any one or more of the foregoing compounds, or a use of the pharmaceutical composition to treat an autoimmune disorder in a subject, wherein the autoimmune disorder is chronic GVHD (cGVHD), acute GVHD (aGVHD), pulmonary fibrosis, idiopathic pulmonary fibrosis, moderate to severe psoriasis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), Crohn's disease, atopic dermatitis, or eczema.
在一些實施例中,本文提供了一種包含任一種或多種前述化合物的醫藥組成物,或所述醫藥組成物治療自體免疫病症的用途。In some embodiments, provided herein is a pharmaceutical composition comprising any one or more of the foregoing compounds, or the use of the pharmaceutical composition to treat an autoimmune disorder.
在一些實施例中,本文提供了一種包含任一種或多種前述化合物的醫藥組成物,或所述醫藥組成物治療慢性GVHD(cGVHD)的用途。In some embodiments, provided herein is a pharmaceutical composition comprising any one or more of the foregoing compounds, or the use of the pharmaceutical composition to treat chronic GVHD (cGVHD).
在一些實施例中,本文提供了一種包含任一種或多種前述化合物的醫藥組成物,或所述醫藥組成物治療急性GVHD(aGVHD)的用途。In some embodiments, provided herein is a pharmaceutical composition comprising any one or more of the foregoing compounds, or the use of the pharmaceutical composition to treat acute GVHD (aGVHD).
在一些實施例中,本文提供了一種包含任一種或多種前述化合物的醫藥組成物,或所述醫藥組成物治療肺纖維化的用途。In some embodiments, provided herein is a pharmaceutical composition comprising any one or more of the foregoing compounds, or the use of the pharmaceutical composition to treat pulmonary fibrosis.
在一些實施例中,本文提供了一種包含任一種或多種前述化合物的醫藥組成物,或所述醫藥組成物治療特發性肺纖維化的用途。In some embodiments, provided herein is a pharmaceutical composition comprising any one or more of the foregoing compounds, or the use of the pharmaceutical composition to treat idiopathic pulmonary fibrosis.
在一些實施例中,本文提供了一種包含任一種或多種前述化合物的醫藥組成物,或所述醫藥組成物治療中度至重度乾癬的用途。In some embodiments, provided herein is a pharmaceutical composition comprising any one or more of the foregoing compounds, or the use of the pharmaceutical composition to treat moderate to severe psoriasis.
在一些實施例中,本文提供了一種包含任一種或多種前述化合物的醫藥組成物,或所述醫藥組成物治療多發性硬化症的用途。In some embodiments, provided herein is a pharmaceutical composition comprising any one or more of the foregoing compounds, or the use of the pharmaceutical composition to treat multiple sclerosis.
在一些實施例中,本文提供了一種包含任一種或多種前述化合物的醫藥組成物,或所述醫藥組成物治療全身性紅斑狼瘡(SLE)的用途。In some embodiments, provided herein is a pharmaceutical composition comprising any one or more of the foregoing compounds, or the use of the pharmaceutical composition to treat systemic lupus erythematosus (SLE).
在一些實施例中,本文提供了一種包含任一種或多種前述化合物的醫藥組成物,或所述醫藥組成物治療克隆氏症的用途。In some embodiments, provided herein is a pharmaceutical composition comprising any one or more of the foregoing compounds, or the use of the pharmaceutical composition to treat Crohn's disease.
在一些實施例中,本文提供了一種包含任一種或多種前述化合物的醫藥組成物,或所述醫藥組成物治療異位性皮膚炎的用途。In some embodiments, provided herein is a pharmaceutical composition comprising any one or more of the aforementioned compounds, or the use of the pharmaceutical composition to treat atopic dermatitis.
在一些實施例中,本文提供了一種包含任一種或多種前述化合物的醫藥組成物,或所述醫藥組成物治療濕疹的用途。In some embodiments, provided herein is a pharmaceutical composition comprising any one or more of the foregoing compounds, or the use of the pharmaceutical composition to treat eczema.
在一些實施例中,接受所述治療的受試者已經進行了作為匹配HSCT的同種異體造血幹細胞移植。在一些實施例中,同種異體造血幹細胞移植是單倍型相合HSCT(haploidentical-HSCT)。In some embodiments, the subject receiving the treatment has undergone an allogeneic hematopoietic stem cell transplant as a matched HSCT. In some embodiments, the allogeneic hematopoietic stem cell transplant is haploidentical-HSCT.
在一些實施例中,基於患者的耐受性,繼續貝魯舒地爾治療直到活躍的cGVHD症狀消退或進展。治療的週期數和持續時間取決於患者。在一些實施例中,在一個或多個28天週期中將貝魯舒地爾投予至患者。In some embodiments, berusudil treatment is continued until active cGVHD symptoms resolve or progress based on the patient's tolerability. The number and duration of treatment depends on the patient. In some embodiments, berusudil is administered to the patient in one or more 28-day cycles.
在一些實施例中,週期數的範圍為3至15。在一些實施例中,週期數的範圍為3至14、3至13、3至12、3至11、3至10、3至9、3至8、3至7、3至6、3至5或3至4。在一些實施例中,週期數的範圍為5至11。在一些實施例中,週期數的範圍為6至12。在一些實施例中,週期數的範圍為5至10、5至9或5至8。在一些實施例中,週期數的範圍為5至7。在一些實施例中,週期數的範圍為5至6。在一些實施例中,週期數為5。在一些實施例中,週期數為6。在一些實施例中,週期數為7。在一些實施例中,週期數為3、4、5、6、7、8、9、10、11、12、13、14或15。In some embodiments, the number of cycles ranges from 3 to 15. In some embodiments, the number of cycles ranges from 3 to 14, 3 to 13, 3 to 12, 3 to 11, 3 to 10, 3 to 9, 3 to 8, 3 to 7, 3 to 6, 3 to 5 Or 3 to 4. In some embodiments, the number of cycles ranges from 5 to 11. In some embodiments, the number of cycles ranges from 6 to 12. In some embodiments, the number of cycles ranges from 5 to 10, 5 to 9, or 5 to 8. In some embodiments, the number of cycles ranges from 5 to 7. In some embodiments, the number of cycles ranges from 5 to 6. In some embodiments, the number of cycles is five. In some embodiments, the number of cycles is six. In some embodiments, the number of cycles is seven. In some embodiments, the number of cycles is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.
在一些實施例中,週期數的範圍為3個週期至失去反應。在一些實施例中,週期數的範圍為4個週期至失去反應。在一些實施例中,週期數的範圍為5個週期至失去反應。在一些實施例中,週期數的範圍為6個週期至失去反應。在一些實施例中,週期數的範圍為7個週期至失去反應。在一些實施例中,週期數的範圍為8個週期至失去反應。在一些實施例中,週期數大於3、4、5、10、15、20、25或30,或者直到實現期望反應。In some embodiments, the number of cycles ranges from 3 cycles to loss of response. In some embodiments, the number of cycles ranges from 4 cycles to loss of response. In some embodiments, the number of cycles ranges from 5 cycles to loss of response. In some embodiments, the number of cycles ranges from 6 cycles to loss of response. In some embodiments, the number of cycles ranges from 7 cycles to loss of response. In some embodiments, the number of cycles ranges from 8 cycles to loss of response. In some embodiments, the number of cycles is greater than 3, 4, 5, 10, 15, 20, 25, or 30, or until the desired reaction is achieved.
在一些實施例中,受試者經歷由Lee症狀量表(LSS)定義的改善。在一些實施例中,受試者經歷LSS得分降低至少7分。在一些實施例中,受試者經歷LSS得分降低至少10分。在一些實施例中,在至少兩次連續評價中保持所述改善。在一些實施例中,在基線和從第2週期第1天開始在每個週期的第1天評價LSS得分。In some embodiments, the subject experiences improvement as defined by the Lee Symptom Scale (LSS). In some embodiments, the subject experiences a decrease in LSS score of at least 7 points. In some embodiments, the subject experiences a decrease in LSS score of at least 10 points. In some embodiments, the improvement is maintained across at least two consecutive evaluations. In some embodiments, LSS scores are assessed at baseline and on Day 1 of each cycle starting on Day 1 of Cycle 2.
在一些實施例中,受試者患有慢性移植物抗宿主病並且已經對於慢性移植物抗宿主病的一條至三條先前系統療法線經歷失敗。在一些實施例中,受試者患有慢性移植物抗宿主病並且已經對於慢性移植物抗宿主病的至少兩條先前系統療法線經歷失敗。在一些實施例中,受試者患有慢性移植物抗宿主病並且已經對於慢性移植物抗宿主病的兩條至五條先前系統療法線經歷失敗。在一些實施例中,受試者已經對於慢性移植物抗宿主病的至少一條、至少兩條、至少三條、至少四條或至少五條先前系統療法線經歷失敗。In some embodiments, the subject has chronic graft-versus-host disease and has experienced failure of one to three prior lines of systemic therapy for chronic graft-versus-host disease. In some embodiments, the subject has chronic graft-versus-host disease and has experienced failure of at least two prior lines of systemic therapy for chronic graft-versus-host disease. In some embodiments, the subject has chronic graft-versus-host disease and has experienced failure of two to five prior lines of systemic therapy for chronic graft-versus-host disease. In some embodiments, the subject has experienced failure of at least one, at least two, at least three, at least four, or at least five prior lines of systemic therapy for chronic graft versus host disease.
在一些實施例中,受試者在貝魯舒地爾之前經歷對移植物抗宿主病的最後治療的完全反應。在一些實施例中,受試者在貝魯舒地爾之前經歷對移植物抗宿主病的最後治療的部分反應。在一些實施例中,受試者在貝魯舒地爾之前在最後一次移植物抗宿主病治療期間經歷疾病穩定。In some embodiments, the subject experienced a complete response to the last treatment for graft-versus-host disease prior to berusudil. In some embodiments, the subject experienced a partial response to the last treatment for graft-versus-host disease prior to begrusudil. In some embodiments, the subject experienced stable disease during the last graft-versus-host disease treatment prior to berusudil.
在一些實施例中,已經中止慢性移植物抗宿主病的先前系統療法線。In some embodiments, a prior line of systemic therapy for chronic graft-versus-host disease has been discontinued.
在一些實施例中,先前系統療法線選自強體松、他克莫司、ECP、西羅莫司、依魯替尼、盧梭替尼、MMF、利妥昔單抗、MTX、環孢素、伊馬替尼、伊沙佐米和奧法木單抗。In some embodiments, the prior line of systemic therapy is selected from the group consisting of prednisone, tacrolimus, ECP, sirolimus, ibrutinib, ruxolitinib, MMF, rituximab, MTX, cyclosporine, Imatinib, ixazomib, and ofatumumab.
在一些實施例中,cGVHD是類固醇難治性(SR)cGVHD。在一些實施例中,受試者是貝魯舒地爾治療之前的最後一條治療線難治的。In some embodiments, the cGVHD is steroid-refractory (SR) cGVHD. In some embodiments, the subject is refractory to the last line of treatment prior to berusudil treatment.
在一些實施例中,受試者正在接受伴隨的皮質類固醇療法。在一些實施例中,伴隨的皮質類固醇療法選自強體松、腎上腺皮質酮、甲基腎上腺皮質酮和布地奈德。在一些實施例中,伴隨的皮質類固醇療法是強體松。在一些實施例中,在至少1個週期的貝魯舒地爾治療後減少伴隨的皮質類固醇療法的劑量。在一些實施例中,在至少1個週期的貝魯舒地爾治療後將伴隨的皮質類固醇療法的劑量減少至少約10%、至少約20%、至少約30%、至少約40%、至少約50%、至少約60%或至少約70%。在一些實施例中,在至少1個週期的貝魯舒地爾治療後將伴隨的皮質類固醇療法的劑量減少至少約10%至約70%、約15%至約65%、約20%至約60%、約30%至約60%、約35%至約60%、約40%至約60%或約45%至約55%。在一些實施例中,在至少1個週期的貝魯舒地爾治療後中止伴隨的皮質類固醇療法。In some embodiments, the subject is receiving concomitant corticosteroid therapy. In some embodiments, the concomitant corticosteroid therapy is selected from the group consisting of prednisone, corticosterone, methyladrenocorticosterone, and budesonide. In some embodiments, the concomitant corticosteroid therapy is prednisone. In some embodiments, the dose of concomitant corticosteroid therapy is reduced after at least 1 cycle of berusudil treatment. In some embodiments, the dose of concomitant corticosteroid therapy is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, or at least about 70%. In some embodiments, the dose of concomitant corticosteroid therapy is reduced after at least 1 cycle of berusudil treatment by at least about 10% to about 70%, about 15% to about 65%, about 20% to about 60%, about 30% to about 60%, about 35% to about 60%, about 40% to about 60%, or about 45% to about 55%. In some embodiments, concomitant corticosteroid therapy is discontinued after at least 1 cycle of berusudil treatment.
在一些實施例中,受試者正在接受伴隨的鈣調磷酸酶抑制劑療法。In some embodiments, the subject is receiving concomitant calcineurin inhibitor therapy.
在一些實施例中,受試者具有至少4個器官受累及。在一些實施例中,受試者具有至少3個器官受累及。在一些實施例中,受試者具有至少2個器官受累及。 組成物和錠劑 In some embodiments, the subject has at least 4 organs involved. In some embodiments, the subject has at least 3 organs involved. In some embodiments, the subject has at least 2 organs involved. Compositions and Tablets
根據另一方面,公開了包括本文所述的化合物作為活性成分的醫藥組成物。這些醫藥組成物包含有效劑量的至少一種本文公開的化合物或所述化合物的醫藥上可接受的鹽,以及還有至少一種醫藥上可接受的賦形劑。According to another aspect, pharmaceutical compositions comprising a compound described herein as an active ingredient are disclosed. These pharmaceutical compositions comprise an effective dose of at least one compound disclosed herein or a pharmaceutically acceptable salt of said compound, and at least one pharmaceutically acceptable excipient.
根據所需藥物形式和投予方法,從本領域通常知識者已知的慣用賦形劑中選擇所述賦形劑。The excipients are selected according to the desired pharmaceutical form and method of administration from customary excipients known to those of ordinary skill in the art.
在這些用於口服、腸胃外(包括皮下、肌內、皮內和靜脈內)、透皮、支氣管或鼻腔投予的醫藥組成物中,可以將在具有常規藥物賦形劑的混合物中的上述式 (I) 的活性成分或其鹽以單位投予形式投予至動物和人類以預防或治療以下病症或疾病。In these pharmaceutical compositions for oral, parenteral (including subcutaneous, intramuscular, intradermal and intravenous), transdermal, bronchial or nasal administration, the above-mentioned ingredients may be mixed with conventional pharmaceutical excipients. The active ingredient of formula (I) or a salt thereof is administered to animals and humans in unit administration form to prevent or treat the following conditions or diseases.
本文所述及/或用於本文所述的方法中的醫藥組成物可以進一步包含醫藥上可接受的載劑/賦形劑。在一些實施例中,所述醫藥上可接受的載劑意指用以幫助向患者遞送API的過程及/或在遞送至患者的運輸期間穩定API的醫藥上可接受的基質、材料、組成物或媒劑,如稀釋劑、固體填充劑、賦形劑或製造助劑(例如潤滑劑、滑石、硬脂酸鎂、硬脂酸鈣或硬脂酸鋅、或硬脂酸)。如以這種意義使用的術語「可接受」意為所述材料與調配物的其他成分相容,並且不會產生對患者有害的不可耐受的副作用。The pharmaceutical compositions described herein and/or used in the methods described herein may further comprise pharmaceutically acceptable carriers/excipients. In some embodiments, the pharmaceutically acceptable carrier means a pharmaceutically acceptable matrix, material, composition used to aid in the process of delivering the API to the patient and/or to stabilize the API during transportation to the patient. or vehicles such as diluents, solid fillers, excipients or manufacturing aids (such as lubricants, talc, magnesium, calcium or zinc stearate, or stearic acid). The term "acceptable" as used in this sense means that the material is compatible with the other ingredients of the formulation and does not produce intolerable side effects that would be harmful to the patient.
本文所考慮的醫藥組成物包括用於口服、腸胃外(包括皮下、肌內、皮內和靜脈內)、透皮、支氣管或鼻腔投予的合適的劑型。Pharmaceutical compositions contemplated herein include suitable dosage forms for oral, parenteral (including subcutaneous, intramuscular, intradermal and intravenous), transdermal, bronchial or nasal administration.
在用於口服投予的固體藥物劑型(膠囊、錠劑、丸劑、散劑、顆粒劑等)中,API可以與至少一種醫藥上可接受的載劑(包括一種或多種醫藥上可接受的賦形劑)混合。In solid pharmaceutical dosage forms (capsules, tablets, pills, powders, granules, etc.) for oral administration, the API may be combined with at least one pharmaceutically acceptable carrier (including one or more pharmaceutically acceptable excipients). agent) mixed.
在一個實施例中,所述化合物被配製成用於口服投予的錠劑。貝魯舒地爾甲磺酸鹽是一種幾乎不溶於水的黃色粉末。可製備貝魯舒地爾錠劑用於口服投予。每個錠劑含有200 mg游離鹼,相當於242.5 mg貝魯舒地爾甲磺酸鹽。錠劑還可含有以下非活性成分:微晶纖維素、羥丙甲纖維素、交聯羧甲基纖維素鈉、膠體二氧化矽和硬脂酸鎂。錠劑薄膜由聚乙烯醇、聚乙二醇、滑石粉、二氧化鈦和黃色氧化鐵組成。每個200 mg錠劑是淡黃色薄膜包衣的橢圓形錠劑,一側具凹入圖案「KDM」,而另一側具凹入圖案「200」。錠劑在室溫20ºC至25ºC(68ºF至77ºF)下儲存;允許在15ºC至30ºC內偏移(59ºF至86ºF)。In one embodiment, the compound is formulated as a lozenge for oral administration. Begrusudil mesylate is a yellow powder that is nearly insoluble in water. Begrusudil tablets may be prepared for oral administration. Each lozenge contains 200 mg free base, equivalent to 242.5 mg berusudil mesylate. Tablets may also contain the following inactive ingredients: microcrystalline cellulose, hypromellose, croscarmellose sodium, colloidal silica, and magnesium stearate. The tablet film consists of polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide and yellow iron oxide. Each 200 mg tablet is a pale yellow film-coated oval-shaped tablet with a debossed pattern of "KDM" on one side and a debossed pattern of "200" on the other side. Tablets are stored at room temperature 20ºC to 25ºC (68ºF to 77ºF); excursions allowed within 15ºC to 30ºC (59ºF to 86ºF).
本文公開的化合物和醫藥組成物可用於抑制ROCK1及/或ROCK2酶(優選ROCK2),並且因此可用於治療由ROCK酶調控的疾病,如自體免疫病症及/或纖維化病症,包括除其他適應症外尤其是GVHD(慢性和急性)、肺纖維化、特發性肺纖維化、中度至重度乾癬、類風濕性關節炎、多發性硬化症、全身性紅斑狼瘡(SLE)、克隆氏症、皮炎(例如,異位性皮膚炎)和濕疹。The compounds and pharmaceutical compositions disclosed herein may be used to inhibit ROCK1 and/or ROCK2 enzymes (preferably ROCK2), and thus may be used to treat diseases modulated by ROCK enzymes, such as autoimmune disorders and/or fibrotic disorders, including, among other indications Extraclinical, especially GVHD (chronic and acute), pulmonary fibrosis, idiopathic pulmonary fibrosis, moderate to severe psoriasis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), Crohn's disease , dermatitis (e.g., atopic dermatitis), and eczema.
以下縮寫可有助於考慮本文的實例和描述。
縮寫
在這項1期兩部分研究中,受試者被投予單次劑量的未標記的貝魯舒地爾口服錠劑(200 mg)、放射性標記的貝魯舒地爾靜脈內(IV)微追蹤輸注(100 μg)和放射性標記的口服膠囊(200 mg)後,評價貝魯舒地爾的藥物動力學、質量平衡和代謝譜。所述研究分2部分進行,具有以下目標:(1) 確定貝魯舒地爾的絕對生物利用度(第1部分),(2) 確定單次口服劑量的放射性標記的貝魯舒地爾後的質量平衡回收(第2部分)以及 (3) 進行代謝物譜分析和鑒定的代謝物的結構闡明(第2部分)。In this Phase 1, two-part study, subjects were administered a single dose of unlabeled berusudil oral lozenge (200 mg), radiolabeled berusudil intravenous (IV) micron The pharmacokinetics, mass balance, and metabolic profile of berusudil were evaluated following follow-up infusion (100 μg) and radiolabeled oral capsules (200 mg). The study was conducted in 2 parts with the following objectives: (1) to determine the absolute bioavailability of begrusudil (Part 1), (2) to determine the mass balance recovery (Part 2) and (3) metabolite profiling and structural elucidation of identified metabolites (Part 2).
基於口服劑量的從時間0至無限的血漿濃度-時間曲線下面積/IV劑量的從時間0至無限的血漿濃度-時間曲線下面積的絕對生物利用度計算為63.7%。放射性標記的IV微追蹤用劑展示了貝魯舒地爾在組織中的低萃取比率和分布。在糞便中回收了大部分的總放射性,其中少量在尿液中回收,這表明貝魯舒地爾極少的腎臟消除。 研究設計 The absolute bioavailability based on the area under the plasma concentration-time curve from time 0 to infinity for the oral dose/the area under the plasma concentration-time curve from time 0 to infinity for the IV dose was calculated to be 63.7%. Radiolabeled IV microtracer demonstrated low extraction rates and distribution of berusudil in tissues. Most of the total radioactivity was recovered in the feces, with a small amount recovered in the urine, indicating minimal renal elimination of berusudil. research design
這是一項在5名30至65歲的健康男性受試者中的單一中心、非隨機化、開放標籤、2部分研究。所有口服劑量均在過夜禁食和用劑當天的標準早餐後投予。This was a single-center, non-randomized, open-label, 2-part study in 5 healthy male subjects aged 30 to 65 years. All oral doses are administered after an overnight fast and a standard breakfast on the day of dosing.
對於絕對生物利用度評價(第1部分),受試者被投予單一口服劑量的200 mg貝魯舒地爾錠劑(治療劑量)1.75小時後,15分鐘IV輸注含有不多於(NMT)37 kBq [ 14C]的100 μg [ 14C]-貝魯舒地爾(在預期最大濃度 [Cmax]時定時發生)。為了確定絕對生物利用度,選擇了微追蹤劑量,因為它不需要具有良好穩定性的IV調配物。此外,由於使用非常低的劑量,無需進一步的非臨床研究,如局部耐受性和一般毒理學研究。 For absolute bioavailability evaluation (Part 1), subjects were administered a single oral dose of 200 mg berusudil lozenge (therapeutic dose) 1.75 hours after a 15-minute IV infusion containing no more than (NMT) 37 kBq [ 14 C] of 100 μg [ 14 C]-berusudil (timed to occur at expected maximum concentration [Cmax]). To determine absolute bioavailability, microtrace dosing was chosen because it does not require an IV formulation with good stability. Furthermore, due to the use of very low doses, further non-clinical studies such as local tolerability and general toxicology studies are not required.
對於質量平衡和代謝譜分析研究(第2部分),從第1部分清除至少7天後,受試者接受了單一口服劑量的含有NMT 9.8 MBq [ 14C]的200 mg [ 14C] -貝魯舒地爾膠囊。基於由英格蘭公共衛生部(Public Health England)進行的人類劑量學計算結果,選擇這種放射性水準,所述計算結果確定了NMT 9.8 MBq的放射性口服劑量對於允許主要樣品的足夠代謝物譜分析是必需的。考慮到第1部分的微追蹤劑量,在研究中受試者接受的總約定有效劑量為3 mSv,這落入國際輻射保護委員會IIb類研究指南(International Commission on Radiological Protection Guidelines for Category IIb studies)內。此外,為了保持在英國放射活性物質管理局諮詢委員會(UK Administration of Radioactive Substances Advisory Committee)批准的放射活性劑量的限制內,將[ 14C]-貝魯舒地爾的靶特異性活性設置為閾值放射活性用劑極限的90%。 藥物動力學樣品收集和分析 第 1 部分的血液採樣。 For the mass balance and metabolic profiling study (Part 2), at least 7 days after washout from Part 1, subjects received a single oral dose of 200 mg [ 14 C]-beta containing NMT 9.8 MBq [ 14 C]. Rusudil capsules. This radioactivity level was chosen based on human dosimetry calculations conducted by Public Health England which determined that an oral dose of radioactivity of NMT 9.8 MBq was necessary to allow adequate metabolite profiling of primary samples of. Taking into account the microtrace dose in Part 1, the total agreed effective dose received by subjects in the study was 3 mSv, which falls within the International Commission on Radiological Protection Guidelines for Category IIb studies . Furthermore, the target-specific activity of [ 14 C]-berusudil was set to a threshold in order to remain within the limits of radioactive doses approved by the UK Administration of Radioactive Substances Advisory Committee 90% of the radioactive dosage limit. Pharmacokinetic Sample Collection and Analysis Part 1 Blood Sampling.
在用劑前和用劑後0.5、1、1.5、2、3、4、5、6、8、10、12、24、36和48小時在乙二胺四乙酸三鉀管中收集口服貝魯舒地爾PK分析的血液樣品。在輸注結束(EOI)後-0.25、-0.16、-0.08、0、0.08、0.16、0.25、0.5、0.75、1、1.5、2、3、4、5、6、8、10、12、22、34和46小時收集血液樣品用於分析IV [ 14C]-貝魯舒地爾PK和總放射性。所有樣品在收集後30分鐘內,在4ºC下透過2000 g離心10分鐘處理為血漿,然後在分析之前冷凍在-70ºC以下。 第 2 部分的血液採樣。 Collect oral Beru in tripotassium EDTA tubes before and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36 and 48 hours after dose. Blood samples for Sudil PK analysis. After End of Infusion (EOI) -0.25, -0.16, -0.08, 0, 0.08, 0.16, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 22, Blood samples were collected at 34 and 46 hours for analysis of IV[ 14C ]-berusudil PK and total radioactivity. All samples were processed into plasma by centrifugation at 2000 g for 10 minutes at 4ºC within 30 minutes of collection and then frozen below -70ºC prior to analysis. Part 2 Blood Sampling.
在用劑前和用劑後1、4、8、12、24、48、72、96、120、144和168小時收集全血樣品(用於總放射性)和血漿樣品(用於代謝物譜分析和鑒定)。在相同的時間點收集血液樣品用於血漿貝魯舒地爾、KD025m1、KD025m2和總放射性分析,其中在用劑後0.5、1.5、2、3、5、6、8、10和36小時收集額外的樣品。將用於總放射性的全血樣品收集到乙二胺四乙酸三鉀管中並且在2ºC至8ºC下儲存以待分析。將用於血漿貝魯舒地爾、KD025m1、KD025m2和總放射性定量以及代謝物譜分析/鑒定的血液樣品類似於第1部分處理,並且在-20ºC(貝魯舒地爾、KD025m1、KD025m2和總放射性樣品)或-70ºC(代謝物譜分析樣品)下冷凍儲存。 第 2 部分 尿液和糞便採樣 Whole blood samples (for total radioactivity) and plasma samples (for metabolite profiling) were collected before dose and 1, 4, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours after dose. and identification). Blood samples for plasma berusudil, KD025m1, KD025m2, and total radioactivity analyzes were collected at the same time points, with additional collections at 0.5, 1.5, 2, 3, 5, 6, 8, 10, and 36 hours postdose. of samples. Whole blood samples for total radioactivity were collected into tripotassium EDTA tubes and stored at 2ºC to 8ºC pending analysis. Blood samples for plasma berusudil, KD025m1, KD025m2, and total radioactivity quantification and metabolite profiling/identification were processed similarly to Part 1 and maintained at -20ºC (berusudil, KD025m1, KD025m2, and total Radioactive samples) or stored frozen at -70ºC (metabolite profiling samples). Part 2 Urine and Stool Sampling
用於總放射性以及代謝物譜分析和鑒定的尿液在用劑之前(當天的第一次排尿)收集,並且在用劑後的0至6、6至12和12至24小時收集,然後每天(24小時)收集直到第8天/出院。將尿液樣品根據間隔收集並且在2ºC至8ºC下儲存以待分析。將糞便從入院收集直到用劑前並且然後每天(24小時)收集直到出院。將糞便樣品根據時間間隔收集並且在-20ºC下儲存以待分析。 分析方法 Urine for total radioactivity and metabolite profiling and identification was collected before dosing (first urination of the day) and 0 to 6, 6 to 12, and 12 to 24 hours after dosing and then daily (24 hours) collected until day 8/discharge. Urine samples were collected at intervals and stored at 2ºC to 8ºC pending analysis. Feces will be collected from admission until just before dosing and then daily (24 hours) until discharge. Fecal samples were collected at time intervals and stored at -20ºC pending analysis. Analytical method
第 1 部分。將貝魯舒地爾血漿樣品使用蛋白質沈澱方法製備用於分析,並且使用定量下限(LLOQ)為10 ng/mL的經驗證的液相層析-串聯質譜(LC- MS/MS)方法進行定量。 part 1 . Begrusudil plasma samples were prepared for analysis using a protein precipitation method and quantified using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with a lower limit of quantification (LLOQ) of 10 ng/mL. .
透過加速質譜法(AMS)確定總[ 14C]-貝魯舒地爾濃度。AMS分析前,將選定的樣品透過液體閃爍計數(LSC)分析以確保放射性水平不會使AMS飽和。將選定的樣品用商購血漿稀釋以確保該濃度落入AMS分析的可接受範圍內。將樣品透過燃燒為CO 2然後還原為石墨而轉化為石墨。然後透過AMS分析石墨目標(單獨受試者的LLOQ為0.00489、0.00557、0.00485、0.00402和0.00372 ng當量/mL)。將所有的 14C資料均基於用劑前[ 14C]-貝魯舒地爾濃度進行背景修正。 Total [ 14 C]-Berusudil concentration was determined by accelerated mass spectrometry (AMS). Prior to AMS analysis, selected samples were analyzed by liquid scintillation counting (LSC) to ensure that radioactivity levels would not saturate the AMS. Selected samples were diluted with commercial plasma to ensure that the concentration fell within the acceptable range for AMS analysis. The sample is converted to graphite by combustion to CO2 and then reduction to graphite. The graphite targets were then analyzed by AMS (individual subject LLOQs were 0.00489, 0.00557, 0.00485, 0.00402, and 0.00372 ng equivalents/mL). All 14 C data were background corrected based on the [ 14 C]-berusudil concentration before administration.
透過高效液相層析與加速質譜(HPLC AMS)方法定量[ 14C]-貝魯舒地爾濃度。 19將血漿中的放射性標記的貝魯舒地爾使用蛋白質沈澱方法製備用於樣品分析,並且隨後進行HPLC。在AMS分析(LLOQ為1.55 pg當量/mL)之前收集對應於[ 14C]-貝魯舒地爾的洗脫部分。 [ 14 C]-Berusudil concentration was quantified by high performance liquid chromatography and accelerated mass spectrometry (HPLC AMS). 19 Radiolabeled berusudil in plasma was prepared for sample analysis using a protein precipitation method and subsequently subjected to HPLC. The elution fraction corresponding to [ 14 C]-berusudil was collected prior to AMS analysis (LLOQ of 1.55 pg equivalents/mL).
第 2 部分。如第1部分中,透過LC-MS/MS定量貝魯舒地爾、KD025m1和KD025m2血漿濃度。 part 2 . As in Part 1, berusudil, KD025m1, and KD025m2 plasma concentrations were quantified by LC-MS/MS.
透過與閃爍液體混合製備總放射性全血樣品、血漿樣品和尿液樣品用於LSC。另外,將全血的等分試樣用AquiGest組織溶解液溶解,並且將血漿樣品與10 mM的磷酸鹽緩衝鹽水混合。在分析之前將尿液和糞便樣品按受試者以時間間隔合併。另外,在LSC之前將糞便樣品使用自動樣品氧化劑燃燒。使用具有自動外標淬滅校正的LSC測量所有樣品中的放射性(2300TR、2900TR和3100TR Tri-Carb,閃爍計數器;PerkinElmer,馬薩諸塞),並且將樣品計數4分鐘。LLOQ被認為是相同類型樣品的背景值的兩倍(1.39 [尿液],23.9 [糞便],35.5 [全血]和30.9 [血漿] ng當量 [游離鹼]/g或mL)。Total radioactive whole blood, plasma, and urine samples were prepared for LSC by mixing with scintillation liquid. Additionally, aliquots of whole blood were lysed with AquiGest tissue lysis buffer, and plasma samples were mixed with 10 mM phosphate buffered saline. Urine and stool samples were pooled by subject at time intervals prior to analysis. Additionally, fecal samples were combusted using an automated sample oxidizer prior to LSC. Radioactivity in all samples was measured using LSC with automatic external standard quenching correction (2300TR, 2900TR, and 3100TR Tri-Carb, scintillation counter; PerkinElmer, Massachusetts), and samples were counted for 4 min. The LLOQ is considered to be twice the background value for the same type of sample (1.39 [urine], 23.9 [feces], 35.5 [whole blood], and 30.9 [plasma] ng equivalents [free base]/g or mL).
為了確定用於代謝物鑒定/分析的最適當的採樣池,根據如上所述獲得的質量平衡資料收集血漿、尿液和糞便樣品。按時間點合併了代表至少80%的血漿總放射性的單獨受試者的血漿樣品,並且在用劑前以及4小時和8小時的時間點跨受試者合併了血漿樣品。用劑前和以0-6小時間隔,從0至24小時合併單獨受試者和跨受試者的尿液樣品。根據時間點合併代表至少80%的血漿總放射性的單獨受試者的糞便樣品,並且在0至24和24至48小時的間隔合併跨受試者的糞便樣品。To determine the most appropriate sampling pool for metabolite identification/analysis, plasma, urine, and fecal samples were collected based on mass balance information obtained as described above. Plasma samples from individual subjects representing at least 80% of total plasma radioactivity were pooled by time point and pooled across subjects before dosing and at the 4 and 8 hour time points. Urine samples from individual subjects and across subjects were pooled from 0 to 24 hours before dosing and at 0-6 hour intervals. Fecal samples from individual subjects representing at least 80% of total plasma radioactivity were pooled according to time point, and fecal samples across subjects were pooled at intervals of 0 to 24 and 24 to 48 hours.
通過LC-MS/MS定量[ 14C]-貝魯舒地爾濃度。然後鑒定占血漿中的> 10%的循環放射性以及占尿液和糞便中的> 10%的劑量的那些放射性組分的化學結構。還鑒定了代表血漿中的< 10%循環放射性以及代表尿液和糞便中的< 10%的劑量的放射性組分。然後使用準確質量正和負離子全掃描以及正離子產物離子分析進行代謝物鑒定。針對以下的存在篩選樣品:貝魯舒地爾,代謝物KD025m1、KD025m2、 O-脫烷基貝魯舒地爾,由O-脫烷基化和羥基化產生的任何潛在代謝物,以及第2階段共軛的代謝物。將任何鑒定的組分與[ 14C]放射層析圖進行比較以鑒定代謝物。將用劑前血漿和尿液池用於校正代謝物鑒定期間的內源組分。 藥物動力學評估 [ 14 C]-Berusudil concentration was quantified by LC-MS/MS. The chemical structures of those radioactive components that account for >10% of the circulating radioactivity in plasma and >10% of the dose in urine and feces are then identified. Radioactive components representing <10% of the circulating radioactivity in plasma and <10% of the dose in urine and feces were also identified. Metabolite identification was then performed using accurate mass positive and negative ion full scans and positive ion product ion analysis. Screen samples for the presence of: berusudil, the metabolites KD025m1, KD025m2, O- dealkylated berusudil, any potential metabolites resulting from O-dealkylation and hydroxylation, and Section 2 Phase conjugated metabolites. Any identified components are compared to [ 14 C] radiochromatograms to identify metabolites. Predose plasma and urine pools were used to correct for endogenous components during metabolite identification. Pharmacokinetic assessment
在Phoenix WinNonlin 8.0版中使用標準非隔室方法計算血漿總放射性、貝魯舒地爾、[ 14C] -貝魯舒地爾(僅第1部分)以及KD025m1和KD025m2(僅第2部分)的PK參數(Certara,新澤西州普林斯頓)。將PK參數估計值用於計算絕對生物利用度和代謝物與母本比率。 Calculation of total plasma radioactivity, berusudil, [ 14C ]-berusudil (part 1 only), and KD025m1 and KD025m2 (part 2 only) using standard non-compartmental methods in Phoenix WinNonlin version 8.0 PK parameters (Certara, Princeton, NJ). PK parameter estimates were used to calculate absolute bioavailability and metabolite to parent ratios.
本研究計算的PK參數是貝魯舒地爾的絕對生物利用度(如通過口服劑量的從時間0至無限的劑量調整的血漿濃度-時間曲線下面積(AUC)(AUC inf,oral)/IV劑量的從時間0至無限的AUC(AUC inf,IV)評估的);所有排泄物中總放射性的質量平衡回收(如通過消除的量 [Ae]、%Ae、累積Ae和累積%Ae評估的);口服貝魯舒地爾、KD025m 1和KD025m 2以及總放射性的各種PK參數;IV [ 14C]-貝魯舒地爾的PK參數;[ 14C] 消除的途徑和速率(血漿和排泄物);總放射性全血:血漿比率;以及血漿和排泄物中的代謝物結構鑒定。 The PK parameter calculated in this study was the absolute bioavailability of berusudil (as the area under the dose-adjusted plasma concentration-time curve (AUC) from time 0 to infinity by oral dose (AUC inf,oral )/IV AUC of dose (as assessed by AUC inf,IV ) from time 0 to infinity); mass balance recovery of total radioactivity in all excreta (as assessed by amount eliminated [Ae], %Ae, cumulative Ae and cumulative %Ae ); Various PK parameters for oral administration of berusudil, KD025m 1 and KD025m 2 , and total radioactivity; PK parameters of IV [ 14 C]-berusudil; [ 14 C] Pathways and rates of elimination (plasma and excretion species); total radioactive whole blood:plasma ratios; and metabolite structure identification in plasma and excreta.
PK群體包括第1部分或第2部分中接受至少1個劑量的貝魯舒地爾並且提供至少1種PK特徵的足夠資料的所有受試者,前提是所述受試者滿足以下標準:(1) 在關鍵時間點沒有缺失的樣品,(2) 沒有影響PK終點的方案偏離,以及 (3) 沒有表明整個劑量未遞送至受試者的不良事件(AE)(例如,嘔吐或輸注部位反應)。The PK population includes all subjects in Part 1 or Part 2 who received at least 1 dose of berusudil and provided sufficient data on at least 1 PK profile, provided the subjects meet the following criteria: ( 1) no missing samples at critical time points, (2) no protocol deviations affecting PK endpoints, and (3) no adverse events (AEs) indicating that the entire dose was not delivered to the subject (e.g., vomiting or infusion site reaction ).
包括在第2部分中接受至少1個劑量的貝魯舒地爾的所有受試者在內的質量平衡群體在尿液/糞便樣品中具有可評價的總放射性濃度,並且沒有可能影響質量平衡分析的方案偏離。 安全性評估 The mass balance population, including all subjects who received at least 1 dose of berusudil in Part 2, had evaluable total radioactivity concentrations in urine/stool samples and had no potential to affect the mass balance analysis deviation from the plan. safety assessment
在整個研究中,透過AE、生命跡象、心電圖、體格檢查和臨床實驗室測試評估了安全性。安全性群體包括在研究的任一部分中接受至少1個劑量的研究藥物(口服或IV)的所有受試者。 結果 受試者處置 Safety was assessed through AEs, vital signs, electrocardiograms, physical examinations, and clinical laboratory testing throughout the study. The safety population included all subjects who received at least 1 dose of study drug (oral or IV) during any part of the study. Result Subject Disposition
在第1部分和第2部分中均招募了五名男性受試者並且向所述受試者用劑。所有受試者均完成了該研究,並且被包括在PK群體和質量平衡群體中。基線人口統計學總結於表1中。受試者的年齡在41與64歲之間(平均年齡,53.0歲),並且大多數受試者是白種人。所有受試者均在體重指數的方案定義的參考範圍內。
表1:受試者人口統計學
單個200 mg口服劑量的貝魯舒地爾然後15分鐘 [
14C]-貝魯舒地爾 IV輸注的平均PK特徵示於圖2(未標記的貝魯舒地爾)和圖3([
14C]-貝魯舒地爾)中。研究的第1部分中針對貝魯舒地爾、[
14C]-貝魯舒地爾和總放射性計算的PK參數呈現於表2中。
表2:第1部分和第2部分中的貝魯舒地爾和總放射性藥物動力學參數的總結
對於IV [ 14C]-貝魯舒地爾輸注,在EOI處達到最大放射性標記的濃度,然後以雙相方式下降。放射性標記的濃度直到最終採樣時間點(EOI後46小時)仍可量化,並且計算所有受試者的終末半衰期(幾何平均值,5.9小時)。 For IV [ 14C ]-berusudil infusion, the maximum radiolabeled concentration is reached at the EOI and then decreases in a biphasic manner. The concentration of the radiolabel remained quantifiable until the final sampling time point (46 hours after EOI), and the terminal half-life was calculated for all subjects (geometric mean, 5.9 hours).
口服用劑後3小時達到口服投予後的峰值貝魯舒地爾濃度,然後到48小時內以雙相的方式下降。報告了所有5名受試者的終末半衰期(幾何平均值,5.3小時)。絕對生物利用度(AUC inf,oral/AUC inf,IV)計算為63.7%。 第 2 部分:質量平衡和排泄。 Peak berusudil concentrations following oral dosing are reached 3 hours after oral dosing and then decrease in a biphasic manner by 48 hours. Terminal half-life is reported for all 5 subjects (geometric mean, 5.3 hours). The absolute bioavailability (AUC inf,oral /AUC inf,IV ) was calculated as 63.7%. Part 2 : Mass balance and excretion.
在排泄物中回收了大部分的放射性(88.5%),其中在糞便中回收84.6%,尿液中回收< 5%的放射性標記的劑量。在用劑後的頭24小時內,分別在糞便和尿液中回收約等於27.4%和3.8%的總放射性。全血:血漿總放射性濃度的範圍為0.53至1.16。第2部分中的貝魯舒地爾和總放射性的PK參數在上文總結於表2中。
第 2 部分:代謝物鑒定和譜分析。試圖對占血漿中10%的循環放射性以及占糞便中> 10%的劑量的放射性組分進行結構鑒定。在血漿、尿液和糞便中鑒定的貝魯舒地爾代謝物呈現於表3中。尿液中沒有占> 10%劑量的單個放射性組分。在血漿中,貝魯舒地爾占總血漿放射性的64%;KD025m2和先前未鑒定的第2相代謝物
O-脫烷基貝魯舒地爾硫酸鹽合併是總血漿放射性的11.5%。尚未在臨床研究中測量的另一種代謝物,貝魯舒地爾葡萄糖醛酸苷,占總血漿放射性的15%。在糞便中,貝魯舒地爾是30%並且KD025m2和O-脫烷基貝魯舒地爾硫酸鹽合併占總樣品放射性的35%。先前未鑒定的貝魯舒地爾二醇(貝魯舒地爾 +2O,+2H)和單羥基貝魯舒地爾在糞便中分別為10%和11%。
表3. 血漿、尿液和糞便中的代謝物鑒定
本研究中發現的貝魯舒地爾的代謝物KD025m1和先前未鑒定的代謝物的化學結構可以展示如下: ; ; KD025m1 貝魯舒地爾葡萄糖醛酸苷 ; ; O-脫烷基貝魯舒地爾硫酸鹽 貝魯舒地爾二醇 ;以及 。 單羥基貝魯舒地爾(血漿) 單羥基貝魯舒地爾(糞便) The chemical structures of berusuudil's metabolite KD025m1 and previously unidentified metabolites discovered in this study can be shown as follows: ; ; KD025m1 berusudil glucuronide ; ; O-dealkylated berusuudil sulfate berusuudil diol ;as well as . Monohydroxyberusudil (plasma) Monohydroxyberusudil (feces)
總體而言,當以200 mg錠劑然後[ 14C]-貝魯舒地爾微追蹤輸注(第1部分)以及以200 mg [ 14C]貝魯舒地爾膠囊(第2部分)投予至健康受試者時,貝魯舒地爾的安全性特徵是如所預期的。在本研究的任一部分中,沒有死亡、嚴重AE、嚴重強度的AE或導致受試者退出的AE。在第1部分中記錄了一例治療中出現的AE(輕度,可能相關的皮疹),而在第2部分中沒有報告治療中出現的AE。所述事件在發生後2.5小時自發消退。在研究的任一部分中,用劑後均未報告臨床上顯著的實驗室、生命跡象、心電圖或體格檢查發現。 Overall, when administered as a 200 mg lozenge followed by a [ 14 C]-begrusudil microtrace infusion (Part 1) and when administered as a 200 mg [ 14 C]-begrusudil capsule (Part 2) In healthy subjects, the safety profile of berusudil was as expected. There were no deaths, serious AEs, AEs of severe intensity, or AEs leading to subject withdrawal in any part of the study. One treatment-emergent AE (mild, possibly related rash) was recorded in Part 1, while no treatment-emergent AEs were reported in Part 2. The event resolved spontaneously 2.5 hours after onset. No clinically significant laboratory, vital sign, electrocardiographic, or physical examination findings were reported following dosing in any part of the study.
本研究評價了在健康男性受試者中口服劑量的未標記錠劑和放射性標記的膠囊以及IV微追蹤的放射性標記的貝魯舒地爾後,貝魯舒地爾在人中的吸收、代謝和排泄特性。如方法部分所述,採用微追蹤方法來準確表徵IV PK特徵,而不會遇到劑量依賴性動力學或用IV調配物進行額外的毒理學研究。使用高靈敏的AMS方法可以精確測量[ 14C] -貝魯舒地爾,而獲取最大資料,而未標記的貝魯舒地爾是透過標準HPLC-MS/MS進行定量。選擇[ 14C]標籤,因為所述標籤可以被容易地引入貝魯舒地爾骨架中的代謝穩定位置,從而確保質量平衡確定和代謝物譜分析。[ 14C]-貝魯舒地爾的合成和分離依賴於與貝魯舒地爾生產中使用的化學過程相同的化學過程。 This study evaluated the absorption, metabolism, and absorption of berusudil in humans following oral doses of unlabeled tablets and radiolabeled capsules and IV microtraced radiolabeled berusudil in healthy male subjects. Excretion properties. As described in the Methods section, a microtracking approach was employed to accurately characterize IV PK characteristics without encountering dose-dependent kinetics or performing additional toxicology studies with IV formulations. [ 14 C]-Begrusudil can be accurately measured using a highly sensitive AMS method to obtain maximum data, while unlabeled Berusudil is quantified by standard HPLC-MS/MS. The [ 14 C] tag was chosen because the tag can be readily introduced into a metabolically stable position within the berusudil backbone, thus ensuring mass balance determination and metabolite profiling. The synthesis and isolation of [ 14C ]-Begrusudil relies on the same chemical processes used in the production of Begrusudil.
在第1部分,口服投予市售的200 mg貝魯舒地爾錠劑後,估計基於劑量調整的AUC inf,oral/AUC inf,IV的絕對生物利用度是63.7%。在IV輸注100 μg [ 14C]-貝魯舒地爾後,IV投予後的總清除率低於典型的肝血流速率,這表明萃取率較低(約等於0.3)。表觀分佈體積高於身體總水量,這表明[ 14C]-貝魯舒地爾分佈到組織中。IV和口服用劑後的半衰期值是相當的,約等於5至6小時,並且與早期臨床試驗中觀察到的值相似。 In Part 1, the absolute bioavailability based on dose-adjusted AUC inf,oral /AUC inf,IV was estimated to be 63.7% after oral administration of the commercially available 200 mg berusuudil tablet. Following IV infusion of 100 μg [ 14 C]-berusuudil, total clearance after IV administration was lower than typical hepatic blood flow rates, indicating a lower extraction rate (approximately equal to 0.3). The apparent volume of distribution is higher than the total body water volume, indicating that [ 14 C]-berusudil is distributed into tissues. Half-life values after IV and oral administration were comparable, approximately 5 to 6 hours, and similar to values observed in early clinical trials.
在第2部分中投予200 mg [ 14C]-貝魯舒地爾膠囊後,在糞便中回收了大部分的總放射性(85%)並且在尿液中回收< 5%,這表明貝魯舒地爾極少的腎臟消除。基於第1部分63.7%的絕對生物利用度和尿液中低放射性回收,[ 14C]-貝魯舒地爾和相關代謝物的主要清除途徑可能是膽及/或腸。總放射性全血:血漿比率的範圍為從0.53至1.16,這表明總放射性幾乎沒有優先分佈到全血的細胞組分中。 Following administration of 200 mg [ 14 C]-berusudil capsules in Part 2, the majority of the total radioactivity (85%) was recovered in feces and <5% in urine, indicating that belusudil Sudil has minimal renal elimination. Based on the absolute bioavailability of 63.7% in Part 1 and the low radioactivity recovery in urine, the primary clearance pathways for [ 14 C]-berusudil and related metabolites are likely to be biliary and/or intestinal. Total radioactivity whole blood:plasma ratios ranged from 0.53 to 1.16, indicating little preferential distribution of total radioactivity into the cellular components of whole blood.
第2部分中血漿中總循環放射性中存在的貝魯舒地爾、KD025m2和KD025m1的濃度表明血漿中可能存在其他循環代謝物。此外,總放射性的半衰期比貝魯舒地爾的半衰期更長(幾何平均值分別為18.0和5.3小時),這進一步支持了其他具有更長消除期的代謝物的存在。確實,使用標準LC-MS/MS代謝物譜分析技術,在本研究中,在人體首次鑒定出除了貝魯舒地爾二醇之外的代謝物葡萄糖醛酸苷和硫酸鹽衍生物。透過本研究開發了人體的貝魯舒地爾代謝途徑,並且呈現於圖3中。The concentrations of berusudil, KD025m2, and KD025m1 present in the total circulating radioactivity in plasma in Part 2 suggest that other circulating metabolites may be present in the plasma. In addition, the half-life of total radioactivity was longer than that of berusudil (geometric means 18.0 and 5.3 hours, respectively), further supporting the existence of other metabolites with longer elimination periods. Indeed, using standard LC-MS/MS metabolite profiling techniques, metabolites other than berusudildiol, glucuronide and sulfate derivatives, were identified in humans for the first time in this study. The metabolic pathway of berusuudil in humans was developed through this study and is presented in Figure 3 .
除了母本、主要代謝物KD025m2和活性次要代謝物KD025m1外,在血漿中鑒定了作為 O-脫烷基貝魯舒地爾硫酸鹽和貝魯舒地爾葡萄糖醛酸苷的其他代謝物。在糞便中,母本、KD025m2、 O-脫烷基貝魯舒地爾硫酸鹽、單羥基貝魯舒地爾和貝魯舒地爾二醇被鑒定為占> 10%的放射性劑量的代謝物。在尿液中未發現占> 10%的劑量的代謝物。 實例 2 :藉由貝魯舒地爾和代謝物進行ROCK1和ROCK2酶促活性的體外研究和抑制 In addition to the parent, major metabolite KD025m2 and the active minor metabolite KD025m1, other metabolites were identified in plasma as O- dealkylated berusudil sulfate and berusudil glucuronide. In feces, parent, KD025m2, O- dealkylated berusuudil sulfate, monohydroxyberusumidil, and berusuudil diol were identified as metabolites accounting for >10% of the radioactivity dose . No metabolites were found in urine accounting for >10% of the dose. Example 2 : In vitro studies and inhibition of ROCK1 and ROCK2 enzymatic activities by berusumidil and metabolites
在從細胞上清液或組織均質物中純化的酶中評價了貝魯舒地爾和主要代謝物(KD025m1和KD025m2)在抑制ROCK2酶促活性方面的作用。The effects of berusudil and the major metabolites (KD025m1 and KD025m2) in inhibiting ROCK2 enzymatic activity were evaluated in enzymes purified from cell supernatants or tissue homogenates.
藉由免疫吸附至用對各種同工酶具特異性的抗體預先塗佈的24孔微量滴定盤,將全長大鼠ROCK1和ROCK2蛋白從各種腫瘤細胞株或組織中分離。透過添加S6激酶基質肽([γ33P]ATP)和研究藥物開始反應,並且在37ºC下培育20分鐘。透過添加磷酸終止反應,並且使用標準方法對放射性進行定量。Full-length rat ROCK1 and ROCK2 proteins were isolated from various tumor cell lines or tissues by immunoadsorption onto 24-well microtiter plates pre-coated with antibodies specific for each isoenzyme. Reactions were initiated by adding S6 kinase matrix peptide ([γ33P]ATP) and study drugs and incubated at 37ºC for 20 minutes. The reaction was stopped by adding phosphoric acid, and the radioactivity was quantified using standard methods.
結果表明貝魯舒地爾抑制ROCK2酶促活性,與抑制ROCK1相比高了大約30倍的抑制作用;即IC 50為其對ROCK1的抑制性作用的小於30分之一。 The results showed that berusudil inhibited the enzymatic activity of ROCK2, and the inhibitory effect was about 30 times higher than that of inhibiting ROCK1; that is, the IC 50 was less than 1/30 of its inhibitory effect on ROCK1.
結果進一步示出了貝魯舒地爾代謝物的抑制活性。表4示出了貝魯舒地爾(KD025)、KD025m1和KD025m2對ROCK酶的抑制性作用的順序。法舒地爾(Fasudil)和Y-27362被列為參考ROCK抑制劑。代謝物KD025m1以與貝魯舒地爾相當的Ki值抑制ROCK2,而第二代謝物KD025m2對ROCK2的抑制是大約6分之一。
表4. 貝魯舒地爾以及代謝物KD025m1和KD025m2對ROCK 2的抑制
儘管已經出於清楚和理解的目的通過說明和實例的方式相當詳細地描述了本發明,但是描述和實例不應被解釋為限制本發明的範圍。在此引用的所有專利和科學文獻的公開內容均明確地通過引用以其整體併入本文。While the invention has been described in considerable detail by way of illustration and example for purposes of clarity and understanding, the description and examples should not be construed as limiting the scope of the invention. The disclosures of all patent and scientific documents cited herein are expressly incorporated by reference in their entirety.
無without
圖1是示出了在投予單個200 mg劑量的貝魯舒地爾然後投予15分鐘[ 14C]-貝魯舒地爾IV輸注後未標記的貝魯舒地爾的平均PK曲線的圖。插圖示出了對數線性標度的資料。 Figure 1 is a graph illustrating the mean PK profile of unlabeled berusudil following administration of a single 200 mg dose of berusudil followed by a 15 minute [ 14C ]-berusudil IV infusion. Figure. The inset shows the data on a log-linear scale.
圖2是示出了在投予單個200 mg劑量的貝魯舒地爾然後投予15分鐘[ 14C]-貝魯舒地爾IV輸注後[ 14C]-貝魯舒地爾的平均PK曲線的圖。插圖示出了對數線性標度的資料。 Figure 2 is a graph showing the mean PK of [ 14C ]-berusudil following administration of a single 200 mg dose of berusudil followed by a 15 minute [ 14C ]-berusudil IV infusion. Curve graph. The inset shows the data on a log-linear scale.
圖3示出了貝魯舒地爾在人體中的代謝途徑。Figure 3 shows the metabolic pathway of berusudil in humans.
無。without.
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