JP6985146B2 - 膵炎処置 - Google Patents
膵炎処置 Download PDFInfo
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- JP6985146B2 JP6985146B2 JP2017544866A JP2017544866A JP6985146B2 JP 6985146 B2 JP6985146 B2 JP 6985146B2 JP 2017544866 A JP2017544866 A JP 2017544866A JP 2017544866 A JP2017544866 A JP 2017544866A JP 6985146 B2 JP6985146 B2 JP 6985146B2
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Description
本出願は、2015年2月27日に出願された米国仮特許出願62/126,386号の利益を主張するものであり、当該文献は参照により全体として本明細書に組み込まれる。
本明細書で言及されるすべての出版物、特許、および特許出願は、あたかも個々の出版物、特許、または特許出願が参照により組み込まれるように具体的かつ個々に指示される程度に、参照により本明細書に組み込まれる。
細胞内カルシウム恒常性は、細胞内カルシウムの濃度及び移動の制御に関係する調節系の合計の結果である。細胞内カルシウム恒常性は、カルシウム結合により、原形質膜からの及び原形質膜へのカルシウムの移動により、及び、例えば小胞体、筋小胞体、ミトコンドリア、及び、エンドソームとリソソームを含むエンドサイトーシス小器官(endocytic organelles)を含む、細胞内小器官の膜にわたるカルシウムの移動により細胞内で、少なくとも部分的に達成される。
1)サイトゾルにおけるIP3の上昇(受容体刺激、又は、IP3自体又は非代謝型アナログIns(2,4,5)P3のような関連する同種によるサイトゾルの透析後);
2)ER膜を透過性にするCa2+イオノフォア(例えばイオノマイシン)の適用;
3)ストアから漏出し、従ってストアの再充填を妨げるCa2+をキレート化する、高濃度のCa2+キレート剤(例えば、EGTA又はBAPTA)による細胞質の透析;
4)タプシガルジン、シクロピアゾン酸、及びジ−tert−ブチルヒドロキノンのような筋形質/小胞体Ca2+−ATPアーゼ(SERCA)阻害剤への曝露;
5)チメロサールのような薬剤による、InsP3の静止レベルに対するIP3受容体の感作;及び
6)N,N,N’,N’−テトラキス(2−ピリジルメチル)エチレンジアミン(TPEN)のような膜透過性金属Ca2+キレート剤の、ストアへの直接の充填。
質量作用を通じて、TPENは、合計のストアCa2+を変化させることなく遊離管腔内Ca2+濃度を低下させ、それによりストアの枯渇に依存するシグナルが生成される。
細胞内カルシウムストアからのカルシウムの放出から結果として生じる小胞体などの細胞内カルシウムストアにおけるカルシウム濃度の減少により、細胞外培地から細胞へのカルシウムの流入のためのシグナルがもたらされる。このカルシウムの流入は細胞質カルシウム濃度の持続した「プラトー」上昇をもたらすものであり、通常、電位依存性原形質膜チャネルには依存せず、カルシウムによるカルシウムチャネルの活性化に関係しない。このカルシウム流入機構は、容量性カルシウム流入(CCE)、カルシウム放出活性化、ストア感受性、又は枯渇感受性(depletion−operated)のカルシウム流入と称される。ストア感受性カルシウム流入は、独特な特性を持つイオン電流として記録され得る。この電流は、ISOC(ストア感受性電流)又はICRAC(カルシウム放出活性化電流)と称される。
ストア感受性カルシウム流入は、細胞内カルシウムストア内のカルシウムのレベルにより調節される。細胞内カルシウムストアは、ストアからのカルシウムの放出を活性化する又はストアへのカルシウムの取り込みを阻害する、生理的又は薬理学的なものであり得る薬剤への感受性を特徴とし得る。異なる細胞が細胞内カルシウムストアの特性付けにおいて研究されてきており、ストアは、IP3、及び、IP3受容体、タプシガルジン、イオノマイシン及び/又は環式のADPリボース(cADPR)に影響を与える化合物を達成するIP3と化合物を含むがこれらに限定されずない、様々な薬剤に敏感なものとして特徴付けられた(例えば、Berridge (1993) Nature 361:315−325; Churchill and Louis (1999) Am. J. Physiol. 276 :C426−C434; Dargie et al. (1990) Cell Regul. 1 :279−290; Gerasimenko et al. (1996) Cell 84 :473−480; Gromoda et al. (1995) FEBS Lett. 360 :303−306; Guse et al. (1999) Nature 398 :70−73)。
細胞中のシグナル伝達プロセスのアゴニスト活性化は、例えば、IP3受容体チャネルの開口部、及びストア感受性カルシウム流入を介した、原形質膜を通る小胞体のカルシウム透過性の劇的な増加に関係し得る。このようなカルシウム透過性の増加は、2つの成分に分離され得るサイトゾルカルシウム濃度の増加に関連する:IP3受容体の活性化中の小胞体からのカルシウム放出の「スパイク」、及び、細胞外培地からの細胞質へのカルシウムの流入から結果として生じるカルシウム濃度の持続的上昇であるプラトー相。刺激の後、約100nMの静止する細胞内遊離カルシウム濃度は、1μMより多く、且つ細胞の微小ドメインにおいてより高く、全体的に増加し得る。細胞は、ミトコンドリア、小胞体、及びゴルジなどの小器官による生理的な緩衝作用を含む、内因性のカルシウムバッファーによりこれらカルシウムシグナルを調節する。内膜中の単輸送体を介したカルシウムのミトコンドリアの取り込みは、大きな負のミトコンドリア膜電位により生じ、蓄積されたカルシウムは、ナトリウム依存性且つそれに依存しない交換体、及び一部の条件下で膜透過性遷移孔(PTP)によりゆっくり放出される。故に、ミトコンドリアは、細胞の活性化の期間中にカルシウムを取り上げることによりカルシウムバッファーとして作用することができ、後にそれをゆっくりと放出することができる。小胞体へのカルシウムの取り込みは、筋形質及び小胞体カルシウムATPアーゼ(SERCA)により調節される。ゴルジへのカルシウムの取り込みは、P型カルシウム輸送ATPアーゼ(PMR1/ATP2C1)により媒介される。加えて、IP3受容体活性化後に放出された著しい量のカルシウムが、原形質膜カルシウムATPアーゼの作用により細胞から押し出されるという証拠が存在する。例えば、原形質膜カルシウムATPアーゼは、ヒトT細胞及びJurkat細胞におけるカルシウム除去のための支配的な機構を提供するが、ナトリウム/カルシウム交換も、ヒトT細胞におけるカルシウム除去に寄与する。カルシウムを貯蔵する小器官内で、カルシウムイオンは、例えばカルセクエストリン、カルレティキュリン、及びカルネキシンなどの、特殊なカルシウム緩衝化タンパク質に結合することができる。加えて、カルシウムスパイクを調節し、且つカルシウムイオンの再分布を助けるサイトゾルには、カルシウム緩衝化タンパク質がある。故に、サイトゾルカルシウム濃度が減らされ得るこれら及び他の機構の何れかに関与する、タンパク質及び他の分子は、細胞質カルシウム緩衝化に関係し、関与し、及び/又はそれを提供するタンパク質である。故に、細胞質カルシウム緩衝化は、SOCチャネルを通った除放性カルシウム流入、又はCa2+放出の突発の期間中に、細胞質Ca2+レベルを調節するのを支援する。細胞質Ca2+レベルの増加、又はストア再充填により、SOCEが不活性化される。
カルシウムストアにおける細胞内の変化に加えて、ストア感受性カルシウム流入は、ストア感受性の変化による、又はそれに加えて、複数の事象に影響を及ぼす。例えば、Ca2+流入は、セリンホスファターゼカルシニューリンを含む、多くのカルモジュリン依存性酵素の活性化を結果としてもたらす。細胞内のカルシウムの増加によるカルシニューリンの活性化は、肥満細胞脱顆粒反応などの急性の分泌プロセスを結果としてもたらす。活性化肥満細胞は、ヒスタミン、ヘパリン、TNFα、及びβ−ヘキソサミニダーゼなどの酵素を含む、予め形成された果粒剤を放出する。B細胞及びT細胞の増殖などの幾つかの細胞事象は、細胞内カルシウムの持続的な増加を要求する持続的なカルシニューリンシグナル伝達を必要とする。多くの転写因子が、NFAT(活性化T細胞の核因子)、MEF2、及びNFκBを含むカルシニューリンにより調節される。NFAT転写因子は、免疫細胞を含む多くの細胞タイプにおいて重要な役割を果たす。免疫細胞において、NFATは、サイトカイン、ケモキネス、及び細胞表面受容体を含む多くの分子の転写を媒介する。NFATのための転写要素は、IL−2、IL−3、IL−4、IL−5、IL−8、IL−13などのサイトカインのプロモータ、同様に腫瘍壊死因子アルファ(TNFα)、果粒球コロニー刺激因子(G−CSF)、及びγ−インターフェロン(γ−IFN)内で見出された。
本明細書には、本明細書に開示される方法、組成物、投与レジメン、及び使用のための組成物に一致する、多くのカルシウムチャネル阻害剤が開示される。幾つかの実施形態において、カルシウムチャネル阻害剤はSOC阻害剤である。幾つかの実施形態において、カルシウムチャネル阻害剤はCRAC阻害剤である。幾つかの実施形態において、カルシウムチャネル阻害剤は、STIM1タンパク質を含むチャネルを阻害する。幾つかの実施形態において、カルシウムチャネル阻害剤は、Orai1タンパク質を含むチャネルを阻害する。幾つかの実施形態において、カルシウムチャネル阻害剤は、Orai2タンパク質を含むチャネルを阻害する。
カルシウムシグナル伝達は、健康な膵臓の活性の中心となる。食品は、アセチルコリン(ACh)とコレシストキニン(cholecyctokinin)(CCK)の放出を刺激し、これらは、膵腺房細胞(PAC)上でホスホリパーゼC(PLC)に結合した受容体と相互に作用する。健康なPACにおいて、ACh又はCCKの受容体は、IP3、1,4,5−イノシトール3リン酸の形成を引き起こし、これは、先端の領域に広まるとともに、制御された拍動性の方式でCa2+を放出するように小胞体(ER)上でIP3受容体を刺激する。Ca2+振動は、膵管への酵素前駆体(プロ酵素)の放出を刺激する。経時的に、ER Ca2+は補充される必要があり、これは細胞の基底外側の領域におけるCRACチャネルの穏やかな活性化により達成される。
急性又は慢性の膵炎は、背中に広がる上腹部又は左上腹部の重度の焼灼痛、吐き気、及び摂食により悪化する嘔吐に関連する。疾病の重症度により、内出血も生じ得る。血圧、心拍数、及び呼吸数は頻繁に上昇するが、脱水症は血圧の上昇ではなく低下に通じ得る。腹部は頻繁に圧痛があるが、膵臓自体における疼痛ほどの痛みは無い。反射的な腸麻痺(Reflex bowel paralysis)は一般的に膵炎の場合に見られ、発熱又は黄疸は珍しくない。膵炎の一般的な症状及び徴候は、背中に広がる重度の上腹部痛(心窩部痛)、吐き気、嘔吐、食欲不振、発熱、悪寒(身ぶるい)、血行動態不安定(ショックを含む)、頻拍症(速い鼓動)、呼吸窮迫、及び腹膜炎を含む。
膵炎、特に急性膵炎は頻繁に、細胞傷害に対する主な反応に依存して、「軽度」、「中度」、又は「重度」として分類される。このような分類は全て、大抵は、トリプシンへのトリプシノゲンを活性化するトリプシノゲン成熟酵素カテプシンでの共局在化によって、膵臓の内部のトリプシノゲンなどの膵臓酵素前駆体の誤った活性化により特徴付けられる。3つの分類は全て、膵臓の炎症及び浮腫を特徴とする。中度及び重度の膵炎は更に、膵壊死、及び膵臓外の器官への二次的な損傷を特徴としており、中度の急性膵炎患者が一時的(<48時間)な臓器不全に悩む一方、重度の急性膵炎患者は持続的(>48時間)な臓器不全に悩む。
本明細書には、CRAC阻害剤などのカルシウムチャネル阻害剤の投与などを介した、膵炎及びその症状の治療上の改善のための組成物及び方法が開示される。幾つかの実施形態において、膵炎は急性膵炎である。幾つかの実施形態において、膵炎は慢性膵炎である。幾つかの実施形態において、ヒトの膵炎の症状を改善する方法が開示される。幾つかの実施形態において、ヒトの膵炎の症状を改善する方法が開示され、該方法は、膵炎の症状の改善を必要とするヒトを特定する工程、及び、前記症状を改善するのに十分な投与量で前記ヒトに細胞内カルシウムシグナル伝達阻害剤を投与する工程を含む。
本明細書には、CRAC阻害剤などのカルシウムチャネル阻害剤の投与などを介した、急性膵炎及びその症状の予防的な改善のための組成物及び方法が開示される。幾つかの実施形態において、ヒトの膵炎の症状を改善する方法が開示される。幾つかの実施形態において、ヒトの膵炎の症状を改善する方法が開示され、該方法は、膵炎の予防的な症状の改善を必要とするヒトを特定する工程、及び、前記症状を予防的に改善するのに十分な投与量で前記ヒトに細胞内カルシウムシグナル伝達阻害剤を投与する工程を含む。
本明細書には、カルシウムチャネル阻害剤と、膵炎に関連した薬物との併用投与のための組成物及び投与レジメンが開示される。幾つかの実施形態において、投与レジメンは、膵臓の活性二対する負の影響に関連した薬物の個体への投与、及び細胞内カルシウムシグナル伝達阻害剤の投与を含む。
病原ウイルスが生物の身体(宿主)に侵入するときに、ウイルス病が生じる。ビリオンと呼ばれる感染性ウイルス粒子は、宿主の感受性細胞に付着し、入る。カルシウムシグナル伝達は、宿主細胞中のウイルスの進入、産生、および伝染を調節し、それによって、ウイルス病が蔓延する。例として、宿主細胞のカルシウムシグナル伝達は、STIM1媒介性およびOrai媒介性のカルシウム流入の活性化によるウイルス病によって引き起こされ、これによって、ウイルスは、宿主細胞内で出芽し、増殖することがさらに可能になる。
Tヘルパー細胞(Th細胞)は免疫系機能に重要である。Th細胞は、ケモカイン、インターフェロン、インターロイキン、リンホカイン、腫瘍壊死因子、またはそれらの組み合わせを含む、T細胞サイトカインを放出することによって免疫系を調節する。Tヘルパー17細胞(Th17)は、炎症性促進性Th細胞のサブセットであり、インターロイキン17(IL−17)のそれらの産生によって定義される。Th17の調節異常は、炎症性および自己免疫性の疾患に関連する。カルシウムシグナル伝達は、Th17分化の調節に重大な役割を果たす。
他に定義されない限り、本明細書で使用されるすべての技術用語および科学用語は、請求される主題が属する一般に理解されるのと同じ意味を有している。本明細書の用語に複数の定義がある場合、このセクションの定義が優先される。本明細書で言及される、すべての特許、特許出願、公報、および公開されたヌクレオチドおよびアミノ酸配列(例えば、GenBankまたは他のデータベースにおいて入手可能な配列)は、引用によって組み込まれる。URLまたは他のそのような特定子あるいはアドレスが言及される場合、そのような特定子が変わる場合があり、インターネットに関する特定の情報が現れたり消えたりする場合があるが、同等な情報をインターネット検索により発見できることが理解される。そのようなものに対する言及は、そのような情報の利用可能性および公的な普及を証拠づけるものである。
代謝に関するさらなる情報は、The Pharmacological Basis of Therapeutics, 9th Edition, McGraw−Hill (1996)から得られる。本明細書に開示される化合物の代謝物は、宿主への化合物の投与および宿主からの組織サンプルの分析によって、または肝細胞を用いた化合物のインビトロでのインキュベーションおよびその結果生じる化合物の分析によって特定され得る。
本明細書で使用されるように、「細胞内カルシウム」は、特定の細胞位置の規定なしで細胞中に位置するカルシウムを指す。対照的に、カルシウムに関連する「サイトゾル(cytosolic)」または「細胞質(cytoplasmic)」は、細胞の細胞質に位置するカルシウムに言及している。
細胞内小器官または貯蔵部位から細胞外培地への、および細胞の細胞質内の1の位置から別の位置へのイオンの移動であり得る。
マウスの膵腺房細胞(PAC)を抽出し、GSK−7975Aの存在下または不存在下で担体(対照)または天然の胆汁酸TLCS(タウロリソコール酸 3−硫酸塩)でインキュベートした。細胞を、ヨウ化プロピジウムと接触させ、細胞壊死に関して分析した。インビトロでの個々の細胞に対するTLCS処置は、胆石、またはインビボでの膵液分泌中の他の閉塞(blockage)の効果を模倣する。
膵臓の組織病理学的進行に対するCRAC阻害剤の効果を評価するために、マウスの急性膵炎モデルを使用した。マウスの膵臓において標準のカルシウムシグナル伝達経路におけるCCK受容体を過剰刺激するために、セルレインを使用する。胆石誘発性急性膵炎において経験されるように、過剰の胆汁酸のシミュレーションによって急性膵炎を誘発するために、TLCSを使用する。アルコール誘発性急性膵炎をシミュレートするために、脂肪酸エチルエステル(FAEE)を使用する。マウスを、急性膵炎用試薬(セルレイン(図2A)、TLCS(図2B)、またはFAEE(図2C))単独で、またはCRAC阻害剤のIC50の10xまたは40xでのCRAC阻害剤GSK−7975Aで処置した。
化合物IおよびGSK−7975Aを、CRACチャネルに対するそれらの阻害効果に関して分析した。Orai1/STIM1およびOrai2/STIM1を含むチャネルを分析した。図3Aで示されるように、化合物Iが、119nMの平均のIC50でOrai1/STIM1チャネルを、および895nMの平均のIC50でOrai2/STIM1チャネルを阻害したと判定された。図3Bで示されるように、GSK−7975Aが、398nMの平均のIC50でOrai1/STIM1チャネルを、および1453nMの平均のIC50でOrai2/STIM1チャネルを阻害したことが判定された。化合物Iは、GSK−7975Aと比較して、Orai1タイプのCRACチャネルに対して約4倍より強力である。両方の化合物は、Orai2タイプのCRACチャネルよりもOrai1に対してより強力である。
マウスPACを分離し、ERへのカルシウム再取り込みに対するCRAC阻害剤の効果に関して分析した。細胞を、シクロピアゾン酸(CPA)単独で(図4A)、またはCRAC阻害剤化合物Iと組み合わせて(図4B)処置して、CRACチャネルを活性化し、Ca2+を放出する。カルシウム放出の15分後、細胞に過剰のカルシウムを提供し、ERへのカルシウム取り込みに関してモニタリングした。CRACの阻害剤で処置した細胞が、カルシウムの再取り込みを実証しないことが観察される。
マウスPACを、CRAC阻害剤化合物I(図5A)またはGSK−7975A(図5B)で処置し、カルシウム取り込みのそれらの速度に関してモニタリングした。両方のCRAC阻害剤は、700nMの阻害剤での処置後に、50%の対照レベルに対するERへのストア感受性カルシウム流入の速度を低下させた。化合物Iは、10mMで再取込みの100%をブロックする。
マウスPACを、10nMのCCKでの処置後に、それらのカルシウム取り込みに関してモニタリングした。細胞をCCKで処置し、その後、細胞に1.8mMのカルシウムを提供し、カルシウム再取り込みをモニタリングした。CRAC阻害剤で予め処置された細胞(図6B)が、未処置の細胞(図6A)と比較して、実質的に縮小したカルシウム再取り込みを実証したことが観察された。化合物Iでの予めの処置は、カルシウム再取り込みを対照のほぼ0%に低下させた。GSK−7975Aは、カルシウム再取り込みを対照の約30%に低下させた。
化合物Iを、多くのサイトカインに対するその阻害効果に関して試験した。サイトカインのINF−ガンマ、IL−4、およびIL−4受容体を腺房細胞上で発現させ、サイトカインのIL−1ベータ、IL−6、IL−10およびTNF−アルファを腺房細胞中で発現させ、およびT細胞機能において重要なサイトカインである、IL−2およびIL−7を、CRAC阻害剤化合物Iの阻害効果に関して試験した。バルクの(bulk)ヒトPBMCのけるT細胞を、48時間、緩衝液+10%の血清中でプレート結合した抗CD3/抗CD28で刺激した、 放出されたサイトカインを、MilliporeのLuminexによって測定した。結果を図7に示す。ヒトPBMCでは、化合物Iは、T細胞において重要な役割を果たす複数のサイトカインの放出を強力に阻害する。
マウスを、予防的にCRAC阻害剤またはビヒクルで処置し、その後、CCKで負荷を与え(challenged)、急性膵炎を引き起こす。予防的に腹腔内(i.p.)投与された化合物Iは、マウスの膵臓(C57B6マウス)においてセルレイン誘発性病態の著しい及び用量依存的な減少をもたらした。この効果は、5mg/kgでの陽性対照CsAより著しく下回っており、用量依存的には増大した。図8Aを参照。該処置は、腹腔内注射後の膵臓における化合物Iレベルの用量比例的な増加を実証し(図8Bを参照)、これは上記の図8Aでの陽性結果に対応している。
マウスを、処置しなかったか(標準)、CCKのみで処置したか(ビヒクル)、または示された用量でCsAまたはCRAC阻害剤と組み合わせたCCKで処置した。血清アミラーゼ活性(図9A)および血清リパーゼ活性(図9B)(IU/L)を測定した。
7回の1時間ごとのセルレインの腹腔内注射を、膵炎を誘発するために行い、1回目の注射の8時間後に動物を屠殺した。化合物Iを、第1のセルレイン注射(予防)の30分前、または3回目の注射(治療)後に腹腔内投与した。CsAを、化合物Iと同じスケジュールで経口(p.o.)投与した。結果を図10に示す。
マウスPACを、500μMのTLCSおよび0.1μMまたは3μMのCRACの阻害剤化合物Iで処置した。サイトゾルカルシウムのレベル(F345/F380比率として測定された)を、各処置のために測定した。TLCSは、細胞内ストア(図示せず)からCa2+を放出し、SOCEを開始する。この実験では、1μMまたは3μMの化合物Iは、TLCS誘発性Ca2+流入を完全にブロックした。結果を図11に示す。
PACからのアミラーゼ放出には、ERカルシウム依存性およびCRAC/サイトゾルカルシウム依存性の要素(component)がある。カルシウム依存性要素を、二価カチオンのキレート剤EGTAの導入によってブロックする。マウスの腺房細胞を、TLCS、および化合物I、GSK−7975Aまたは化合物IIなどの、ビヒクル、EGTA、またはCRAC阻害剤で処置し、アミラーゼ放出に関してモニタリングした。CRAC阻害剤がアミラーゼ放出に対するそれらの効果においてEGTAを模倣したことが観察されている。図12を参照。
マウスPACを、DMSO、DMSO+500μMのTLCS、またはDMSO+500μMのTLCS+1μMのCRACの阻害剤化合物Iで処置した。細胞壊死を、%PI取り込みとして測定した。CRAC阻害剤化合物Iは、マウスPACにおいてTLCS誘発性壊死を阻害する。
この第II相試験の目的は、急性膵炎および付随するSIRSの患者における、化合物I、GSK−7975A、および化合物IIなどのカルシウムシグナル伝達阻害剤、または化合物Aの群から選択される化合物の単回および繰り返しの静脈注射の安全性、耐性、PK、PD、および効果を調査することにある。
包含基準:
・ すべての被験体は、試験の間に、および男性に関しては投薬後少なくとも12週間および女性に関しては投薬後32週間、妊娠していないことを保証するために、許容可能な避妊を使用しなければならない。
・ 55−95kgの体重範囲に加えて、18.5−35kg/m2の範囲内の肥満度指数。
・ 被験体は、インフォームドコンセントを与えることができなければならず、試験要件およびタイムテーブルに従うことができる;
・ 18歳以上の男性および女性の被験体が適格である。
・ 被験体は、急性膵炎の発症が生涯で初めでなければならない。
・ 急性膵炎の診断は、以下の3つの基準の2つに基づいていなければならない:(1)典型的な上腹部痛;(2)正常上限の少なくとも3倍の血清アミラーゼ及び/又はリパーゼの上昇;(3)造影剤強調のCTスキャンまたは腹部の超音波画像が急性膵炎の変化を実証している。
・ 被験体は、現在の膵炎発症のアルコール性、高トリグリセリド血症、または胆汁性の病因を支持する病歴を実証しなければならない(胆管膵炎については、超音波画像は試験のスクリーニング時に結石閉塞(stone obstruction)を除外しなければならない)。
・ 被験体は、3以上のBISAPスコアを実証しなければならない。
・ 試験の処置開始が、症状発症の48時間以内に可能である。
・ 翌週に侵襲的胆管内介入(例えばERCP)の高い可能性。
・ 膵炎の再発。
・ 試験のエントリーでの膵臓壊死のCT証拠。
・ 重度の慢性腎不全(30mL/分の処方での又は腎透析に依存した、腎臓病における食事の変更)。
・ クラスIIまたはそれ以上のニューヨーク心臓協会心不全。
・ 酸素依存性の慢性閉塞性肺疾患(COPD)。
・ 肝硬変。
・ 重度の貧血症(8g/dL未満のヘモグロビン)。
・ 試験のエントリー時に35%未満の又は45%を超えるヘマトクリット(試験の処置が症状の発症の48時間以内に開始する限り、無作為化の前にヘマトクリットを補正するために、流体が投与され得る)。
・ 試験のエントリーでの250IU/Lを超える血清アラニンアミノトランスフェラーゼ。
・ 試験のエントリーでの上行性胆管炎の臨床的疑い。
・ 活動性の消化管出血。
・ 寛解中ではない現在の悪性腫瘍(皮膚の基底細胞癌以外)。
・ 精神状態の変化。
・ 現在の授乳または妊娠。
・ 十分且つ有効な避妊方法を使用しようとしない、出産の可能性のある女性(閉経後2年未満または外科的に滅菌されていない)。
・ 治験薬の成分に対する既知の過敏性。
・ 研究者またはスポンサーとの依存した関係性。
・ 本臨床試験の間、または本臨床試験の開始前30日以内の治験薬の試験への参加。
・ C反応性タンパク質の血清中濃度。
・ 48時間でのSIRSの変化。
・ 血液アミラーゼおよびリパーゼのレベル。
・ 慣例の安全性臨床検査によるこの患者集団におけるCRAC阻害剤の安全性。
・ 身体検査および生命徴候のモニタリング、ECGおよび有害事象報告。
・ 他の血漿炎症性マーカー(インターロイキン−6、マトリックスメタロプロテアーゼ9、腫瘍壊死因子アルファなど)に対するCRAC阻害剤の効果。
・ 膵炎の臨床経過に対するCRAC阻害剤の効果(急性膵炎の重症度に対するベッドサイド指標(BISAP)、全身性炎症反応症候群(SIRS)および急性・慢性生理学的分類評価II(APACHE II)のスコアなどの、臨床的な評定尺度の変化、および造影剤強調の腹部コンピューター断層撮影(CT)に基づく)
・ 経時的臓器不全評価(SOFA)スコアの進行
・ 多臓器機能不全スコア(MODS)の進行
・ 全身性炎症反応症候群の進行
・ 炎症性および抗炎症性のメディエーター(IL−1RA、IL−10、IL−6、IL−18、TNF−α、ICAM−1、IL−10など)の進行。
・ 高い依存性または集中治療室および入院の長さに対する注意の増大。
弱毒生Candid−1 JUNVに感染したVeroE6細胞を、DMSO、DMSO+500μMのTLCS、DMSO+500μMのTLCS+1μMのCRAC阻害剤化合物I、DMSO+500μMのTLCS+10μMの化合物I、DMSO+500μMのTLCS+25μMの化合物I、またDMSO+500μMのTLCS+50μMの化合物Iで処置する。これらの細胞から産生された感染性ビリオンを、フォーカス形成アッセイ中で定量化する。JUNVフォーカスの列挙(Enumeration)は、化合物Iによる処置後のJUNVウイルス産生の統計的に有意な、用量依存性の減少を明らかにしている。
Th1、Th2、およびTh17の極性化状態下で培養されたナイーブな刺激されたネズミT細胞を、DMSO、DMSO+500μMのTLCS、またはDMSO+500μMのTLCS+1μMのCRACの阻害剤化合物Iで処置する。ストア感受性Ca2+流入(SOCE)を各処置において定量化する。化合物Iは、ナイーブ、Th1、またはTh2の細胞におけるよりも、分化されたTh17細胞において、より強くSOCEをブロックする。さらに、Th17細胞によるIL−17A産生は、化合物Iの存在下において、Th1およびTh2の細胞による、それぞれ、IFN−γおよびIL−4の産生と比較したときに、より深刻に影響される。
Claims (23)
- ヒトの膵炎の症状を改善するための薬物の製造における、細胞内カルシウムシグナル伝達阻害剤、またはその薬学的に許容可能な塩、またはその薬学的に許容可能な溶媒和物の使用であって、
前記症状は慢性膵炎の症状であり、前記細胞内カルシウムシグナル伝達阻害剤は、N−(5−(6−クロロ−2,2−ジフルオロベンゾ[d][1,3]ジオキソール−5−イル)ピラジン−2−イル)−2−フルオロ−6−メチルベンズアミドである、使用。 - 前記細胞内カルシウムシグナル伝達阻害剤はSOCチャネル阻害剤である、請求項1に記載の使用。
- 前記細胞内カルシウムシグナル伝達阻害剤はCRACチャネル阻害剤である、請求項1に記載の使用。
- 前記細胞内カルシウムシグナル伝達阻害剤はSTIM1タンパク質を含むチャネルを阻害する、請求項1に記載の使用。
- 前記細胞内カルシウムシグナル伝達阻害剤はOrai1タンパク質を含むチャネルを阻害する、請求項1に記載の使用。
- 前記細胞内カルシウムシグナル伝達阻害剤は、Orai2タンパク質を含むチャネルを阻害する、請求項1に記載の使用。
- 前記症状の少なくとも1つは、腺房細胞の変性、凝固壊死、炎症、または浮腫を含む、請求項1−6のいずれか1つに記載の使用。
- 前記症状は、膵臓の炎症と浮腫、背中への放散上腹部痛、背中への放散左上腹部痛、悪心、嘔吐、摂食により悪化する嘔吐、高い心拍数、頻脈、高い呼吸数、高血圧、血圧低下、脱水、腹部圧痛、発熱、悪寒、腹膜炎、血行動態不安定、および反射性の腸麻痺の少なくとも1つを含む、請求項1−6のいずれか1つに記載の使用。
- 前記症状は炎症反応を含む、請求項1−6のいずれか1つに記載の使用。
- 前記症状は、膵壊死と膵臓外の臓器の損傷の少なくとも1つを含む、請求項1−6のいずれか1つに記載の使用。
- 前記症状は、持続性腹痛、消化異常、脂肪の吸収不良、食物摂取中の疼痛、体重減少、血清アミラーゼ活性の上昇、血清リパーゼ活性の上昇、CRPの炎症マーカーの上昇、重炭酸産生の低下、糞便のエラスターゼレベルの上昇、血清トリプシノゲンレベルの上昇、膵臓の石灰化、血清ビリルビンレベルの上昇、およびアルカリホスファターゼレベルの上昇の少なくとも1つを含む、請求項1−6のいずれか1つに記載の使用。
- 前記症状は、ESRレベルの上昇、IgG4レベルの上昇、リウマチ因子の増大、ANA抗体の存在、および、抗平滑筋抗体の存在の少なくとも1つを含む、請求項1−6のいずれか1つに記載の使用。
- 前記症状は、脂肪便、100gの脂肪食での24時間にわたる7グラム以上の糞便または糞便脂肪排泄物のズダン化学染色、および糞便サンプル中の200μg/g未満の値の糞便のエラスターゼの少なくとも1つを含む、請求項1−6のいずれか1つに記載の使用。
- 前記症状は、腹痛、血中アミラーゼレベルの増加、血液リパーゼレベルの増加、膵臓の拡大、悪心、嘔吐、内出血、腸麻痺、発熱、黄疸、体重減少、および心拍数の上昇の少なくとも1つを含む、請求項1−10のいずれか1つに記載の使用。
- 前記症状は、アミラーゼの血中濃度の上昇を含む、請求項1−10のいずれか1つに記載の使用。
- 前記症状は、リパーゼの血中濃度の上昇を含む、請求項1−10のいずれか1つに記載の使用。
- 前記症状は、コンピューター断層撮影(CT)スキャンによる壊死の発見物を含む、請求項1−10のいずれか1つに記載の使用。
- 前記症状は早熟な消化酵素活性化を含む、請求項1−10のいずれか1つに記載の使用。
- 前記早熟な消化酵素活性化は前記ヒトの膵臓において生じる、請求項18に記載の使用。
- 前記酵素はトリプシンを含む、請求項18に記載の使用。
- 化学名N−(5−(6−クロロ−2,2−ジフルオロベンゾ[d][1,3]ジオキソール−5−イル)ピラジン−2−イル)−2−フルオロ−6−メチルベンズアミドを有する化合物またはその薬学的に許容される塩。
- 化学名N−(5−(2,5−ジメチルベンゾ[d]オキサゾール−6−イル)チアゾール−2−イル)−2,3,6−トリフルオロベンズアミドを有する化合物またはその薬学的に許容される塩。
- ヒトの膵炎の症状を改善するための薬物の製造における使用のための医薬組成物であって、前記症状は慢性膵炎の症状であり、前記医薬組成物は、請求項21または22に記載の化合物またはその薬学的に許容される塩、および薬学的に許容可能な賦形剤を含む、医薬組成物。
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Families Citing this family (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10703722B2 (en) | 2010-04-27 | 2020-07-07 | Calcimedica, Inc. | Compounds that modulate intracellular calcium |
SG11201609974PA (en) * | 2014-06-03 | 2016-12-29 | Actelion Pharmaceuticals Ltd | Pyrazole compounds and their use as t-type calcium channel blockers |
JP6985146B2 (ja) | 2015-02-27 | 2021-12-22 | カルシメディカ,インク. | 膵炎処置 |
AU2016306301B2 (en) | 2015-08-07 | 2021-02-11 | Calcimedica, Inc. | Use of CRAC channel inhibitors for the treatment of stroke and traumatic brain injury |
JP2020506179A (ja) * | 2017-01-26 | 2020-02-27 | カルシメディカ,インク. | Cracチャネル阻害剤組成物 |
US10961242B2 (en) | 2017-05-17 | 2021-03-30 | Legochem Biosciences, Inc. | Compounds as autotaxin inhibitors and pharmaceutical compositions comprising the same |
KR101798840B1 (ko) | 2017-05-17 | 2017-11-17 | 주식회사 레고켐 바이오사이언스 | 신규 오토탁신 저해 화합물 및 이를 함유하는 약제학적 조성물 |
CN110063945B (zh) * | 2019-04-15 | 2021-07-09 | 温州医科大学 | 一种用于急性胰腺炎治疗的胆红素纳米颗粒及其制备方法 |
JP2022532875A (ja) * | 2019-05-06 | 2022-07-20 | カルシメディカ,インク. | Cracチャネル阻害剤の合成 |
CN114206850B (zh) * | 2019-09-25 | 2024-01-26 | 辰欣药业股份有限公司 | 作为crac抑制剂的2h-苯并吡喃衍生物 |
CN115835878A (zh) * | 2020-03-20 | 2023-03-21 | 钙医学公司 | 治疗急性肺损伤和急性呼吸窘迫综合征的方法和组合物 |
CA3179405A1 (en) * | 2020-05-20 | 2021-11-25 | Kenneth A. Stauderman | Methods and compositions for treating acute kidney injury |
US11413270B2 (en) * | 2020-06-22 | 2022-08-16 | Novmetapharma Co., Ltd. | Method for the treatment of pancreatitis |
WO2022032238A1 (en) * | 2020-08-07 | 2022-02-10 | Board Of Regents, The University Of Texas System | Methods and compositions for pancreatic cancer evaluation and treatment |
CN117098756A (zh) * | 2021-02-25 | 2023-11-21 | 辰欣药业股份有限公司 | 一种环丙基取代的苯并呋喃类化合物的晶型及其制备方法 |
CN113424795B (zh) * | 2021-05-24 | 2022-09-09 | 四川大学华西医院 | 一种急性胰腺炎动物模型的构建方法和用途 |
CN113903460A (zh) * | 2021-12-10 | 2022-01-07 | 中国医学科学院北京协和医院 | 一种预测重症急性胰腺炎的系统及其应用 |
AU2023209914A1 (en) * | 2022-01-20 | 2024-08-08 | Calcimedica, Inc. | Methods and compositions for treating inflammation injury in the lungs |
CN114522157B (zh) * | 2022-02-23 | 2023-08-15 | 重庆大学 | 钙离子螯合剂在制备用于提高血管内皮细胞吞噬能力的制剂中的应用 |
Family Cites Families (88)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5424289A (en) | 1977-07-26 | 1979-02-23 | Mitsubishi Chem Ind Ltd | Production of spherical diatomaceous earth carrier |
WO1998006719A1 (en) | 1996-08-09 | 1998-02-19 | Boehringer Ingelheim Pharmaceuticals, Inc. | 4-substituted beta-carbolines as immunomodulators |
AU751139B2 (en) | 1997-10-13 | 2002-08-08 | Astellas Pharma Inc. | Amide derivative |
US6022884A (en) | 1997-11-07 | 2000-02-08 | Amgen Inc. | Substituted pyridine compounds and methods of use |
CA2327185A1 (en) | 1998-04-08 | 1999-10-14 | Abbott Laboratories | Pyrazole inhibitors of cytokine production |
CA2332957A1 (en) | 1998-06-05 | 1999-12-09 | Boehringer Ingelheim Pharmaceuticals, Inc. | Substituted 1-(4-aminophenyl)pyrazoles and their use as anti-inflammatory agents |
US20010044445A1 (en) | 1999-04-08 | 2001-11-22 | Bamaung Nwe Y. | Azole inhibitors of cytokine production |
ATE397590T1 (de) | 1999-08-20 | 2008-06-15 | Dow Agrosciences Llc | Fungizide heterocyclische aromatische amide und deren zusammensetzungen, verfahren zu deren anwendung und herstellung |
JP3910319B2 (ja) | 1999-09-13 | 2007-04-25 | 株式会社小糸製作所 | 自動車用灯具 |
EP1143013A1 (en) | 2000-04-03 | 2001-10-10 | Warner-Lambert Company | Methods and compositions for screening Icrac modulators |
CA2445712A1 (en) | 2001-05-31 | 2002-12-05 | Cellegy Pharmaceuticals, Inc. | Store operated calcium influx inhibitors and methods of use |
GB0225554D0 (en) | 2002-11-01 | 2002-12-11 | Syngenta Participations Ag | Chemical compounds |
ES2571779T3 (es) | 2002-12-13 | 2016-05-26 | Ym Biosciences Australia Pty | Inhibidores de cinasa a base de nicotinamida |
EP1575918A2 (en) | 2002-12-19 | 2005-09-21 | Neurogen Corporation | Substituted biaryl-4-carboxylic acid arylamide analogues as capsaicin receptor modulators |
WO2004078995A2 (en) | 2003-03-04 | 2004-09-16 | Neurogenetics, Inc. | Methods of modulating and of identifying agents that modulate intracellular calcium |
ES2358426T3 (es) | 2003-07-23 | 2011-05-10 | Synta Pharmaceuticals Corporation | Compuestos para la inflamación y usos inmunorrelacionados. |
DE102004005785A1 (de) | 2004-02-06 | 2005-08-25 | Bayer Cropscience Ag | 2-Halogenfuryl/thienyl-3-carboxamide |
WO2006006569A1 (ja) | 2004-07-12 | 2006-01-19 | Nihon Nohyaku Co., Ltd. | フェニルピリジン類又はその塩類、これらを有効成分とする除草剤及びその使用方法 |
MX2007003342A (es) | 2004-09-21 | 2007-06-05 | Synta Pharmaceutical Corp | Compuestos para inflamacion y usos relacionados con trastornos inmunitarios. |
US8557861B2 (en) | 2004-09-28 | 2013-10-15 | Mast Therapeutics, Inc. | Low oil emulsion compositions for delivering taxoids and other insoluble drugs |
TWI441819B (zh) | 2005-01-07 | 2014-06-21 | Synta Pharmaceuticals Corp | 用於炎症及免疫相關用途之化合物 |
NZ590359A (en) | 2005-01-25 | 2012-08-31 | Synta Pharmaceuticals Corp | Pyrazine compounds for inflammation and immune-related uses |
AU2006208043B2 (en) | 2005-01-25 | 2012-09-20 | Synta Pharmaceuticals Corp. | Thiophene compounds for inflammation and immune-related uses |
MX2007009888A (es) | 2005-02-17 | 2007-10-16 | Synta Pharmaceuticals Corp | Compuestos para el tratamiento de trastornos proliferativos. |
EP2527337A1 (en) | 2005-04-14 | 2012-11-28 | Bristol-Myers Squibb Company | Inhibitors of 11-beta hydroxysteroid dehydrogenase type I |
WO2007035874A1 (en) | 2005-09-21 | 2007-03-29 | Bristol-Myers Squibb Company | Oral administration of n-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-1,3-thiazole-5-carboxamide and salts thereof |
NL2000284C2 (nl) | 2005-11-04 | 2007-09-28 | Pfizer Ltd | Pyrazine-derivaten. |
CN102775396B (zh) | 2005-11-08 | 2014-10-08 | 沃泰克斯药物股份有限公司 | Atp-结合弹夹转运蛋白的杂环调控剂 |
CN101309669A (zh) | 2005-11-15 | 2008-11-19 | 巴克斯特国际公司 | 脂氧合酶抑制剂的组合物 |
EP2368912B1 (en) | 2006-01-05 | 2017-05-03 | Children's Medical Center Corporation | Regulators of NFAT |
TW200806290A (en) | 2006-01-25 | 2008-02-01 | Synta Pharmaceuticals Corp | Substituted biaryl compounds for inflammation and immune-related uses |
WO2007087441A2 (en) | 2006-01-25 | 2007-08-02 | Synta Pharmaceuticals Corp. | Substituted aromatic compounds for inflammation and immune-related uses |
WO2007087443A2 (en) | 2006-01-25 | 2007-08-02 | Synta Pharmaceuticals Corp. | Vinyl-phenyl derivatives for inflammation and immune-related uses |
AU2007208227A1 (en) | 2006-01-25 | 2007-08-02 | Synta Pharmaceuticals Corp. | Phenyl and pyridyl compounds for inflammation and immune-related uses |
EP1983980A4 (en) | 2006-01-25 | 2010-05-05 | Synta Pharmaceuticals Corp | THIAZOL AND THIADIAZOL COMPOUNDS FOR USES IN RELATION TO INFLAMMATION AND IMMUNITY |
JP5430944B2 (ja) | 2006-01-31 | 2014-03-05 | シンタ ファーマシューティカルズ コーポレーション | 炎症および免疫関連用途のためのピリジルフェニル化合物 |
US7951824B2 (en) | 2006-02-17 | 2011-05-31 | Hoffman-La Roche Inc. | 4-aryl-pyridine-2-carboxyamide derivatives |
CA2645434A1 (en) | 2006-03-20 | 2007-09-27 | Synta Pharmaceutical Corp. | Benzoimidazolyl-parazine compounds for inflammation and immune-related uses |
JP2009530409A (ja) | 2006-03-23 | 2009-08-27 | シンタ ファーマシューティカルズ コーポレーション | 炎症及び免疫関連使用用のベンゾイミダゾリル−ピリジン化合物 |
EP2004627A2 (en) | 2006-04-10 | 2008-12-24 | Arena Pharmaceuticals, Inc. | 3-pyridinyl-pyrazole derivatives as modulators of the 5-ht2a serotonin receptor useful for the treatment of disorders related thereto |
PL3026044T3 (pl) | 2006-06-26 | 2019-04-30 | Akebia Therapeutics Inc | Inhibitory prolilo-hydroksylazy i sposoby ich użycia |
US20080207641A1 (en) | 2006-11-13 | 2008-08-28 | Synta Pharmaceuticals Corp. | Cyclohexenyl-aryl compounds for inflammation and immune-related uses |
JP2010519206A (ja) | 2007-02-16 | 2010-06-03 | シンタ ファーマシューティカルズ コーポレーション | 炎症及び免疫関連使用のための置換縮合環化合物 |
WO2008148108A1 (en) | 2007-05-24 | 2008-12-04 | Calcimedica, Inc. | Calcium channel proteins and uses thereof |
TW200914440A (en) | 2007-08-01 | 2009-04-01 | Synta Pharmaceuticals Corp | Vinyl-aryl derivatives for inflammation and immune-related uses |
US8435996B2 (en) | 2007-08-01 | 2013-05-07 | Synta Pharmaceuticals Corp. | Heterocycle-aryl compounds for inflammation and immune-related uses |
WO2009020642A1 (en) | 2007-08-09 | 2009-02-12 | Merck & Co., Inc. | Pyridine carboxamide orexin receptor antagonists |
RU2465272C2 (ru) | 2007-09-10 | 2012-10-27 | КалсиМедика, Инк. | Соединения, моделирующие внутриклеточный кальций |
WO2009089305A1 (en) | 2008-01-07 | 2009-07-16 | Synta Pharmaceuticals Corp. | Compounds for inflammation and immune-related uses |
FR2927330B1 (fr) | 2008-02-07 | 2010-02-19 | Sanofi Aventis | Derives de 5,6-bisaryl-2-pyridine-carboxamide, leur preparation et leur application en therapeutique comme antagonistes des recepteurs a l'urotensine ii |
US20110003859A1 (en) | 2008-02-29 | 2011-01-06 | Array Biopharma Inc. | N- (6-aminopyridin-3-yl) -3- (sulfonamido) benzamide derivatives as b-raf inhibitors for the treatment of cancer |
JP2011515376A (ja) | 2008-03-20 | 2011-05-19 | ツェー・エス・エル・ベーリング・ゲー・エム・ベー・ハー | 病的血栓形成に必須であるカルシウムセンサSTIM1及び血小板SOCチャネルOrai1(CRACM1) |
US20100016598A1 (en) | 2008-07-16 | 2010-01-21 | Wyeth | Alpha7 nicotinic acetylcholine receptor inhibitors |
CA2734500A1 (en) | 2008-08-27 | 2010-03-11 | Calcimedica Inc. | Compounds that modulate intracellular calcium |
US8524763B2 (en) | 2008-09-22 | 2013-09-03 | Calcimedica, Inc. | Inhibitors of store operated calcium release |
WO2010034011A2 (en) | 2008-09-22 | 2010-03-25 | Calcimedica, Inc. | Phenylthiophenyldihydrobenzothiazepine inhibitors of store operated calcium release |
TW201018667A (en) | 2008-10-01 | 2010-05-16 | Synta Pharmaceuticals Corp | Compounds for inflammation and immune-related uses |
CA2739322A1 (en) | 2008-10-01 | 2010-04-08 | Synta Pharmaceuticals Corp. | Compounds for inflammation and immune-related uses |
US20110230536A1 (en) | 2008-10-24 | 2011-09-22 | Calcimedica, Inc. | Phenylpyrazole inhibitors of store operated calcium release |
UY32571A (es) | 2009-04-24 | 2010-11-30 | Glaxo Group Ltd | Compuestos derivados de pirazol amida |
JP2012524754A (ja) | 2009-04-24 | 2012-10-18 | グラクソ グループ リミテッド | Cracチャネル阻害剤としてのピラゾールおよびトリアゾ−ルカルボキサミド |
US20100316725A1 (en) | 2009-05-27 | 2010-12-16 | Elan Pharma International Ltd. | Reduction of flake-like aggregation in nanoparticulate active agent compositions |
US8618307B2 (en) | 2009-09-16 | 2013-12-31 | Calcimedica, Inc. | Compounds that modulate intracellular calcium |
US8377970B2 (en) | 2009-10-08 | 2013-02-19 | Rhizen Pharmaceuticals Sa | Modulators of calcium release-activated calcium channel |
US8993612B2 (en) * | 2009-10-08 | 2015-03-31 | Rhizen Pharmaceuticals Sa | Modulators of calcium release-activated calcium channel and methods for treatment of non-small cell lung cancer |
WO2011063277A1 (en) | 2009-11-20 | 2011-05-26 | Amgen Inc. | Anti-orai1 antigen binding proteins and uses thereof |
US8476006B2 (en) | 2009-11-30 | 2013-07-02 | National Center For Biological Sciences | Store-operated calcium cellular assay |
CN102753527B (zh) | 2010-02-02 | 2014-12-24 | 诺华股份有限公司 | 用作crf受体拮抗剂的环己基酰胺衍生物 |
US10703722B2 (en) | 2010-04-27 | 2020-07-07 | Calcimedica, Inc. | Compounds that modulate intracellular calcium |
JP6112486B2 (ja) | 2010-04-27 | 2017-04-12 | カルシメディカ,インク. | 細胞内カルシウムを調節する化合物 |
EP2563759B1 (en) | 2010-04-27 | 2022-04-06 | Calcimedica, Inc. | Compounds that modulate intracellular calcium |
US9079891B2 (en) * | 2010-08-27 | 2015-07-14 | Calcimedica, Inc. | Compounds that modulate intracellular calcium |
US9604978B2 (en) | 2011-05-03 | 2017-03-28 | Synta Pharmaceuticals Corp. | Compounds for inflammation and immune-related uses |
WO2012170931A2 (en) | 2011-06-10 | 2012-12-13 | Calcimedica, Inc. | Compounds that modulate intracellular calcium |
WO2012170951A2 (en) | 2011-06-10 | 2012-12-13 | Calcimedica, Inc. | Compounds that modulate intracellular calcium |
US9856240B2 (en) | 2011-10-19 | 2018-01-02 | Calcimedica, Inc. | Compounds that modulate intracellular calcium |
CA2853469A1 (en) * | 2011-10-19 | 2013-04-25 | Calcimedica, Inc. | Compounds that modulate intracellular calcium |
JP5936350B2 (ja) | 2011-12-27 | 2016-06-22 | キヤノン株式会社 | 新規有機化合物 |
WO2013164769A1 (en) * | 2012-05-02 | 2013-11-07 | Lupin Limited | Substituted pyridine compounds as crac modulators |
WO2014043715A1 (en) * | 2012-09-17 | 2014-03-20 | Calcimedica, Inc. | Compounds that modulate intracellular calcium |
US9512116B2 (en) | 2012-10-12 | 2016-12-06 | Calcimedica, Inc. | Compounds that modulate intracellular calcium |
US9725463B2 (en) | 2013-06-21 | 2017-08-08 | Lupin Limited | Substituted heterocyclic compounds as CRAC modulators |
JP6985146B2 (ja) | 2015-02-27 | 2021-12-22 | カルシメディカ,インク. | 膵炎処置 |
AU2016306301B2 (en) | 2015-08-07 | 2021-02-11 | Calcimedica, Inc. | Use of CRAC channel inhibitors for the treatment of stroke and traumatic brain injury |
JP2020506179A (ja) | 2017-01-26 | 2020-02-27 | カルシメディカ,インク. | Cracチャネル阻害剤組成物 |
US20210338630A1 (en) | 2018-10-04 | 2021-11-04 | The Trustees Of Indiana University | Methods to treat renal disorders using calcium channel inhibitors |
CN115835878A (zh) | 2020-03-20 | 2023-03-21 | 钙医学公司 | 治疗急性肺损伤和急性呼吸窘迫综合征的方法和组合物 |
CA3179405A1 (en) | 2020-05-20 | 2021-11-25 | Kenneth A. Stauderman | Methods and compositions for treating acute kidney injury |
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