CN102276698B - MC4-R cyclopeptide agonist and application thereof - Google Patents
MC4-R cyclopeptide agonist and application thereof Download PDFInfo
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- CN102276698B CN102276698B CN201010196955.0A CN201010196955A CN102276698B CN 102276698 B CN102276698 B CN 102276698B CN 201010196955 A CN201010196955 A CN 201010196955A CN 102276698 B CN102276698 B CN 102276698B
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 239000002287 radioligand Substances 0.000 description 1
- 238000001525 receptor binding assay Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical compound [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 230000036299 sexual function Effects 0.000 description 1
- 229960003310 sildenafil Drugs 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 230000036642 wellbeing Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/665—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
- C07K14/68—Melanocyte-stimulating hormone [MSH]
- C07K14/685—Alpha-melanotropin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- Engineering & Computer Science (AREA)
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- General Chemical & Material Sciences (AREA)
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- Diabetes (AREA)
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- Peptides Or Proteins (AREA)
Abstract
The invention belongs to the field of pharmaceutical chemical engineering and relates to a cyclic peptide shown as a formula (1), or stereoisomers thereof, or physiological-toxicity-free salts thereof. The compounds have MC4-R (Melanocortin 4 Receptors) excitation activity. The invention also relates to a medicinal composition containing the compounds and application of the compounds to preparation of medicaments for treating obesity or sexual dysfunction and other diseases.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and relates to a cyclopeptide derivative shown in a formula (1), or a stereoisomer thereof, or a physiologically-nontoxic salt thereof; these compounds have MC4-R agonistic activity. The invention also relates to a pharmaceutical composition containing the compounds and application of the compounds in preparing medicaments for treating diseases such as obesity or sexual dysfunction.
R-Xaa 1-cyclo (Xaa2-Xaa3-Xaa4-Arg-Trp-Xaa5) -Z formula (1)
Background
With the change of society and life style, some diseases such as obesity or sexual dysfunction are increasingly highlighted. Among them, obesity is one of the well-known factors causing common diseases such as arteriosclerosis, hypertension, heart disease and I I-type diabetes, and sexual dysfunction seriously affects physical and mental health and family well-being of patients.
Only mild obesity increases the probability of diabetes, hypertension and other diseases, however, only a few effective drugs for treating obesity are currently on the market, such as Sibutramine (Sibutramine) and Orlistat (Orlistat), and the drugs are not free from rebound after stopping taking the drugs; first-line drugs for the treatment of sexual dysfunction are phosphodiesterase inhibitors such as sildenafil, but these drugs are not effective in female patients and some patients report a gradual loss of response. Therefore, the development of new drugs for treating obesity and sexual dysfunction is necessary and urgent, and has a very broad prospect.
alpha-MSH is an endogenous linear tridecapeptide derived from Proopiomelanocortin (POMC). As early as 50 s in the 20 th century, it was discovered that central administration of alpha-MSH to dogs, monkeys, cats, and rabbits caused sexual excitement, and that the mechanism of action was mediated by MC 4-R. Research has shown that MC4-R agonists have potential application values in the treatment of obesity and sexual dysfunction (Van PL, Martin W J, Howard A D, et al. A role for the melanocortin 4 receptor in the sexual function, Proceedings of the National Academy of Sciences of the United states of America, 2002, 99 (17): 11381-11386; Martin W J, Macintyre D. melanocortin receptors and choice function. European rotation, 2004, 45 (6): 706-713.).
The alpha-MSH is a linear tridecapeptide, the C end is an amide structure, and the N end is acetylated. The primary structure of α -MSH is as follows:
Ac-Ser1-Tyr2-Ser3-Met4-Glu5-His6-Phe7-Arg8-Trp9-Gly10-Lys11-Pro12-Val13-NH2
later, the minimal active sequence of alpha-MSH was found to be His6-Phe7-Arg8-Trp9. Around this effectThe synthesis of a series of compounds, including linear peptides and cyclic peptides, has been designed to have certain effects in the treatment of obesity and sexual dysfunction. Among them, the cyclic heptapeptide MC4-R agonist PT-141(Bremelanotide) developed by the american company Palatin is undergoing phase II clinical study (Palatin Technologies inc., PRESS RELEASE on Febrary 16, 2010.). At present, no compound of the type is available on the market due to short half-life or large toxic and side effects (such as causing blood pressure rise). Therefore, it is very important to properly improve the half-life of the compound and reduce the toxic and side effects while maintaining the activity.
Disclosure of Invention
One aspect of the present invention relates to a cyclic peptide derivative represented by formula (1), or a stereoisomer thereof, or a physiologically nontoxic salt thereof,
R-Xaa 1-cyclo (Xaa2-Xaa3-Xaa4-Arg-Trp-Xaa5) -Z formula (1)
Wherein,
r is selected from H and R1C(O)-、R1R2C(O)-、R1R2NC (O) -, Biotin-t-butyloxycarbonyl (Boc) represented by formula (2), and turnip-methoxycarbonyl (Fmoc), wherein R is1And R2Each independently selected from H, halogen, substituted or unsubstituted C1-C6Straight or branched alkyl, substituted or unsubstituted C2-C6Straight or branched alkenyl or alkynyl, substituted or unsubstituted C1-C6Straight or branched alkoxy, substituted or unsubstituted C1-C6Straight or branched alkylthio, substituted or unsubstituted C2-C6Straight or branched alkenyl or alkynyloxy, substituted or unsubstituted C2-C6Linear or branched alkenylthio or alkynylthio, C3-C8Cycloalkyl radical, C3-C8Cycloalkenyl radical, C6-C14Aryl, heteroaryl, and C3-C8A heterocyclic group;
Z is-OH or-NR3R4Wherein R is3、R4Each independently is H-, R1-、R1R2C(O)-、R1R2NC (O) -, wherein R1And R2As defined above;
xaa1 is selected from the group consisting of leucine residue (Leu), isoleucine residue (Ile), norleucine residue (Nle), and the structure-NH- (CH) in L or D form2)n1-CO-, wherein n1 is an integer from 1 to 5;
xaa2 is selected from structures represented by formula (3) -formula (6) in L or D form, wherein n2-n5 are each independently selected from integers of 1-5;
Xaa3 is His in L or D form, or a structure shown in formula (7), wherein R is5Is selected from R1、-NR1R2、-NHC(O)NR1R2、-C(O)NR1R2and-NH-C (O) R1Wherein R is1And R2As defined above;
Xaa4 is of type D
Wherein R is6Is selected from R1、-NR1R2、-NHC(O)NR1R2、-C(O)NR1R2and-NH-C (O) R1Wherein R is1And R2As defined above;
xaa5 is selected from the structures of formula (8) -formula (11) in L or D form, wherein n6-n9 are each independently selected from integers of 1-5;
The cyclopeptide derivative shown in the formula (1), or the stereoisomer or the physiologically-nontoxic salt thereof has good MC4-R agonistic activity and good stability. Therefore, the cyclic peptide derivative shown in the formula (1), or the stereoisomer thereof, or the physiologically-nontoxic salt thereof can be used as a medicament for treating obesity and related diseases and sexual dysfunction. Wherein, the "ring" means a ring formed by an amide bond (-CO-NH-) or a disulfide bond (-S-).
In one embodiment of the invention, R is Biotin-, Xaa2 is a structure represented by formula (3) or (4) and Xaa5 is a structure represented by formula (8) or (9), or Xaa2 is a structure represented by formula (5) or (6) and Xaa5 is a structure represented by formula (10) or (11).
In one embodiment of the invention, R is selected from H-, R1C(O)-、R1R2C (o) -, tert-butoxycarbonyl (Boc), and turnip methoxycarbonyl (Fmoc), Xaa2 is a structure represented by formula (3) and Xaa5 is a structure represented by formula (9), or Xaa2 is a structure represented by formula (4) and Xaa5 is a structure represented by formula (8) or formula (9), or Xaa2 is a structure represented by formula (5) and Xaa5 is a structure represented by formula (11), or Xaa2 is a structure represented by formula (6) and Xaa5 is a structure represented by formula (10) or formula (11).
In one embodiment of the present invention, said R5Is H.
In one embodiment of the invention, R is acetyl (AC-) or Biotin-, Z is-NH2Xaa1 is L-Nle or Aca, Xaa2 is L-Asp, L-Cys, L-hCys, NAsp or NhCys, Xaa5 is L-Lys, L-Cys, L-hCys, NLys or NhCys, Xaa3 is L-His or L-Tal, Xaa4 is D-Phe or D-Cpa.
In one embodiment of the invention, the cyclic peptide derivative is selected from the following compounds:
(1) Ac-Nle-Ring (Asp-His-DPhe-Arg-Trp-NLys) -NH2
(2) Ac-Nle-cyclo (NAsp-His-DPhe-Arg-Trp-Lys) -NH2
(3) Ac-Nle-ring (NAsp-His-DPhe-Arg-Trp-NLys) -NH2
(4) Ac-Nle-cyclo (Cys-His-DPhe-Arg-Trp-NhCys) -NH2
(5) Ac-Nle-cyclo (NhCys-His-DPhe-Arg-Trp-Cys) -NH2
(6) Ac-Nle-cyclo (NhCys-His-DPhe-Arg-Trp-NhCys) -NH2
(7) Ac-Nle-Loop (Asp-His-DCpa-Arg-Trp-NLys) -NH2
(8) Ac-Nle-cyclo (NAsp-His-DCpa-Arg-Trp-Lys) -NH2
(9) Ac-Nle-Loop (NAsp-His-DCpa-Arg-Trp-NLys) -NH2
(10) Ac-Nle-cyclo (Cys-His-DCpa-Arg-Trp-NhCys) -NH2
(11) Ac-Nle-cyclo (NhCys-His-DCpa-Arg-Trp-Cys) -NH2
(12) Ac-Nle-cyclo (NhCys-His-DCpa-Arg-Trp-NhCys) -NH2
(13) Biotin-Nle-Ring (Asp-His-DPhe-Arg-Trp-NLys) -NH2
(14) Biotin-Nle-ring (NAsp-His-DPhe-Arg-Trp-Lys) -NH2
(15) Biotin-Nle-ring (NAsp-His-DPhe-Arg-Trp-NLys) -NH2
(16) Biotin-Nle-cyclo (Cys-His-DPhe-Arg-Trp-NhCys) -NH2
(17) Biotin-Nle-Ring (NhCys-His-DPhe-Arg-Trp-Cys) -NH2
(18) Biotin-Nle-Ring (NhCys-His-DPhe-Arg-Trp-NhCys) -NH2
(19) Biotin-Nle-Ring (Asp-His-DCpa-Arg-Trp-NLys) -NH2
(20) Biotin-Nle-ring (NAsp-His-DCpa-Arg-Trp-Lys) -NH2
(21) Biotin-Nle-Loop (NAsp-His-DCpa-Arg-Trp-NLys) -NH2
(22) Biotin-Nle-Ring (Cys-His-DCpa-Arg-Trp-NhCys) -NH2
(23) Biotin-Nle-Ring (NhCys-His-DCpa-Arg-Trp-Cys) -NH2
(24) Biotin-Nle-Ring (NhCys-His-DCpa-Arg-Trp-NhCys) -NH2
(25) Biotin-Nle-ring (Asp-His-D)Phe-Arg-Trp-Lys)-NH2
(26) Biotin-Nle-cyclo (Cys-His-DPhe-Arg-Trp-Cys) -NH2
(27) Biotin-Nle-Ring (hCys-His-DPhe-Arg-Trp-Cys) -NH2
(28) Biotin-Nle-cyclo (Cys-His-DPhe-Arg-Trp-hCys) -NH2
(29) Biotin-Nle-Ring (hCys-His-DPhe-Arg-Trp-hCys) -NH2
(30) Biotin-Nle-Ring (Asp-His-DCpa-Arg-Trp-Lys) -NH2
(31) Biotin-Nle-Ring (Cys-His-DCpa-Arg-Trp-Cys) -NH2
(32) Biotin-Nle-Ring (hCys-His-DCpa-Arg-Trp-Cys) -NH2
(33) Biotin-Nle-Ring (Cys-His-DCpa-Arg-Trp-hCys) -NH2
(34) Biotin-Nle-Ring (hCys-His-DCpa-Arg-Trp-hCys) -NH2
(35) Ac-Nle-cyclo (Asp-Tal-DPhe-Arg-Trp-NLys) -NH2
(36) Ac-Nle-cyclo (NAsp-Tal-DPhe-Arg-Trp-Lys) -NH2
(37) Ac-Nle-ring (NAsp-Tal-DPhe-Arg-Trp-NLys) -NH2
(38) Ac-Nle-cyclo (Cys-Tal-DPhe-Arg-Trp-NhCys) -NH2
(39) Ac-Nle-cyclo (NhCys-Tal-DPhe-Arg-Trp-Cys) -NH2
(40) Ac-Nle-cyclo (NhCys-Tal-DPhe-Arg-Trp-NhCys) -NH2
(41) Ac-Nle-Loop (Asp-Tal-DCpa-Arg-Trp-NLys) -NH2
(42) Ac-Nle-cyclo (NAsp-Tal-DCpa-Arg-Trp-Lys) -NH2
(43) Ac-Nle-ring (NAsp-Tal-DCpa-Arg-Trp-NLys) -NH2
(44) Ac-Nle-cyclo (Cys-Tal-DCpa-Arg-Trp-NhCys) -NH2
(45) Ac-Nle-cyclo (NhCys-Tal-DCpa-Arg-Trp-Cys) -NH2
(46) Ac-Nle-cyclo (NhCys-Tal-DCpa-Arg-Trp-NhCys) -NH2
(47) Biotin-Nle-Ring (Asp-Tal-DPhe-Arg-Trp-NLys) -NH2
(48) Biotin-Nle-ring (NAsp-Tal-DPhe-Arg-Trp-Lys) -NH2
(49) Biotin-Nle-ring (NAsp-Tal-DPhe-Arg-Trp-NLys) -NH2
(50) Biotin-Nle-Ring (Cys-Tal-DPhe-Arg-Trp-NhCys) -NH2
(51) Biotin-Nle-Ring (NhCys-Tal-DPhe-Arg-Trp-Cys) -NH2
(52) Biotin-Nle-Ring (NhCys-Tal-DPhe-Arg-Trp-NhCys) -NH2
(53) Biotin-Nle-Ring (Asp-Tal-DCpa-Arg-Trp-NLys) -NH2
(54) Biotin-Nle-ring (NAsp-Tal-DCpa-Arg-Trp-Lys) -NH2
(55) Biotin-Nle-ring (NAsp-Tal-DCpa-Arg-Trp-NLys) -NH2
(56) Biotin-Nle-Ring (Cys-Tal-DCpa-Arg-Trp-NhCys) -NH2
(57) Biotin-Nle-Ring (NhCys-Tal-DCpa-Arg-Trp-Cys) -NH2
(58) Biotin-Nle-Ring (NhCys-Tal-DCpa-Arg-Trp-NhCys) -NH2
(59) Biotin-Nle-Ring (Asp-Tal-DPhe-Arg-Trp-Lys) -NH2
(60) Biotin-Nle-Ring (Cys-Tal-DPhe-Arg-Trp-Cys) -NH2
(61) Biotin-Nle-Ring (hCys-Tal-DPhe-Arg-Trp-Cys) -NH2
(62) Biotin-Nle-Ring (Cys-Tal-DPhe-Arg-Trp-hCys) -NH2
(63) Biotin-Nle-Ring (hCys-Tal-DPhe-Arg-Trp-hCys) -NH2
(64) Biotin-Nle-Ring (Asp-Tal-DCpa-Arg-Trp-Lys) -NH2
(65) Biotin-Nle-Ring (Cys-Tal-DCpa-Arg-Trp-Cys) -NH2
(66) Biotin-Nle-Ring (hCys-Tal-DCpa-Arg-Trp-Cys) -NH2
(67) Biotin-Nle-Ring (Cys-Tal-DCpa-Arg-Trp-hCys) -NH2
(68) Biotin-Nle-Ring (hCys-Tal-DCpa-Arg-Trp-hCys) -NH2
(69) Ac-Aca-cyclo (Asp-His-DPhe-Arg-Trp-NLys) -NH2
(70) Ac-Aca-cyclo (NAsp-His-DPhe-Arg-Trp-Lys) -NH2
(71) Ac-Aca-cyclo (NAsp-His-DPhe-Arg-Trp-NLys) -NH2
(72) Ac-Aca-cyclo (Cys-His-DPhe-Arg-Trp-NhCys) -NH2
(73) Ac-Aca-cyclo (NhCys-His-DPhe-Arg-Trp-Cys) -NH2
(74) Ac-Aca-cyclo (NhCys-His-DPhe-Arg-Trp-NhCys) -NH2
(75) Ac-Aca-cyclo (Asp-His-DCpa-Arg-Trp-NLys) -NH2
(76) Ac-Aca-cyclo (NAsp-His-DCpa-Arg-Trp-Lys) -NH2
(77) Ac-Aca-cyclo (NAsp-His-DCpa-Arg-Trp-NLys) -NH2
(78) Ac-Aca-Loop (Cys-His-DCpa)-Arg-Trp-NhCys)-NH2
(79) Ac-Aca-cyclo (NhCys-His-DCpa-Arg-Trp-Cys) -NH2
(80) Ac-Aca-cyclo (NhCys-His-DCpa-Arg-Trp-NhCys) -NH2
(81) Biotin-Aca-ring (Asp-His-DPhe-Arg-Trp-NLys) -NH2
(82) Biotin-Aca-cyclo (NAsp-His-DPhe-Arg-Trp-Lys) -NH2
(83) Biotin-Aca-ring (NAsp-His-DPhe-Arg-Trp-NLys) -NH2
(84) Biotin-Aca-cyclo (Cys-His-DPhe-Arg-Trp-NhCys) -NH2
(85) Biotin-Aca-cyclo (NhCys-His-DPhe-Arg-Trp-Cys) -NH2
(86) Biotin-Aca-cyclo (NhCys-His-DPhe-Arg-Trp-NhCys) -NH2
(87) Biotin-Aca-ring (Asp-His-DCpa-Arg-Trp-NLys) -NH2
(88) Biotin-Aca-cyclo (NAsp-His-DCpa-Arg-Trp-Lys) -NH2
(89) Biotin-Aca-ring (NAsp-His-DCpa-Arg-Trp-NLys) -NH2
(90) Biotin-Aca-cyclo (Cys-His-DCpa-Arg-Trp-NhCys) -NH2
(91) Biotin-Aca-cyclo (NhCys-His-DCpa-Arg-Trp-Cys) -NH2
(92) Biotin-Aca-cyclo (NhCys-His-DCpa-Arg-Trp-NhCys) -NH2
(93) Biotin-Aca-cyclo (Asp-His-DPhe-Arg-Trp-Lys) -NH2
(94) Biotin-Aca-cyclo (Cys-His-DPhe-Arg-Trp-Cys) -NH2
(95) Biotin-Aca-cyclo (hCys-His-DPhe-Arg-Trp-Cys) -NH2
(96) Biotin-Aca-cyclo (Cys-His-DPhe-Arg-Trp-hCys) -NH2
(97) Biotin-Aca-cyclo (hCys-His-DPhe-Arg-Trp-hCys) -NH2
(98) Biotin-Aca-ring (Asp-His-DCpa-Arg-Trp-Lys) -NH2
(99) Biotin-Aca-cyclo (Cys-His-DCpa-Arg-Trp-Cys) -NH2
(100) Biotin-Aca-cyclo (hCys-His-DCpa-Arg-Trp-Cys) -NH2
(101) Biotin-Aca-cyclo (Cys-His-DCpa-Arg-Trp-hCys) -NH2
(102) Biotin-Aca-cyclo (hCys-His-DCpa-Arg-Trp-hCys) -NH2
(103) Ac-Aca-cyclo (Asp-Tal-DPhe-Arg-Trp-NLys) -NH2
(104) Ac-Aca-cyclo (NAsp-Tal-DPhe-Arg-Trp-Lys) -NH2
(105) Ac-Aca-cyclo (NAsp-Tal-DPhe-Arg-Trp-NLys) -NH2
(106) Ac-Aca-cyclo (Cys-Tal-DPhe-Arg-Trp-NhCys) -NH2
(107) Ac-Aca-cyclo (NhCys-Tal-DPhe-Arg-Trp-Cys) -NH2
(108) Ac-Aca-cyclo (NhCys-Tal-DPhe-Arg-Trp-NhCys) -NH2
(109) Ac-Aca-cyclo (Asp-Tal-DCpa-Arg-Trp-NLys) -NH2
(110) Ac-Aca-cyclo (NAsp-Tal-DCpa-Arg-Trp-Lys) -NH2
(111) Ac-Aca-cyclo (NAsp-Tal-DCpa-Arg-Trp-NLys) -NH2
(112) Ac-Aca-cyclo (Cys-Tal-DCpa-Arg-Trp-NhCys) -NH2
(113) Ac-Aca-cyclo (NhCys-Tal-DCpa-Arg-Trp-Cys)-NH2
(114) Ac-Aca-cyclo (NhCys-Tal-DCpa-Arg-Trp-NhCys) -NH2
(115) Biotin-Aca-ring (Asp-Tal-DPhe-Arg-Trp-NLys) -NH2
(116) Biotin-Aca-cyclo (NAsp-Tal-DPhe-Arg-Trp-Lys) -NH2
(117) Biotin-Aca-ring (NAsp-Tal-DPhe-Arg-Trp-NLys) -NH2
(118) Biotin-Aca-cyclo (Cys-Tal-DPhe-Arg-Trp-NhCys) -NH2
(119) Biotin-Aca-cyclo (NhCys-Tal-DPhe-Arg-Trp-Cys) -NH2
(120) Biotin-Aca-cyclo (NhCys-Tal-DPhe-Arg-Trp-NhCys) -NH2
(121) Biotin-Aca-ring (Asp-Tal-DCpa-Arg-Trp-NLys) -NH2
(122) Biotin-Aca-ring (NAsp-Tal-DCpa-Arg-Trp-Lys) -NH2
(123) Biotin-Aca-ring (NAsp-Tal-DCpa-Arg-Trp-NLys) -NH2
(124) Biotin-Aca-cyclo (Cys-Tal-DCpa-Arg-Trp-NhCys) -NH2
(125) Biotin-Aca-cyclo (NhCys-Tal-DCpa-Arg-Trp-Cys) -NH2
(126) Biotin-Aca-cyclo (NhCys-Tal-DCpa-Arg-Trp-NhCys) -NH2
(127) Biotin-Aca-cyclo (Asp-Tal-DPhe-Arg-Trp-Lys) -NH2
(128) Biotin-Aca-cyclo (Cys-Tal-DPhe-Arg-Trp-Cys) -NH2
(129) Biotin-Aca-cyclo (hCys-Tal-DPhe-Arg-Trp-Cys) -NH2
(130) Biotin-Aca-cyclo (Cys-Tal-DPhe-Arg-Trp-hCys) -NH2
(131) Biotin-Aca-cyclo (hCys-Tal-DPhe-Arg-Trp-hCys) -NH2
(132) Biotin-Aca-cyclo (Asp-Tal-DCpa-Arg-Trp-Lys) -NH2
(133) Biotin-Aca-cyclo (Cys-Tal-DCpa-Arg-Trp-Cys) -NH2
(134) Biotin-Aca-cyclo (hCys-Tal-DCpa-Arg-Trp-Cys) -NH2
(135) Biotin-Aca-cyclo (Cys-Tal-DCpa-Arg-Trp-hCys) -NH2
(136) Biotin-Aca-cyclo (hCys-Tal-DCpa-Arg-Trp-hCys) -NH2
Preferably, the present invention is selected from the above compounds 1, 2, 3, 4, 5, 10, 14, 16, 17, 20, 23, 25, 27, 30, 32, 36, 38, 39, 42, 45, 48, 54, 69, 70, 71, 72, 73, 78, 82, 84, 85, 88, 91, 93, 95, 98, 100, 104, 106, 107, 110, 112, 113, 116, and 122.
Another aspect of the present invention relates to a pharmaceutical composition comprising any one of the above cyclic peptide derivatives, or stereoisomers thereof, or physiologically non-toxic salts thereof, optionally together with a pharmaceutically acceptable carrier or adjuvant.
A further aspect of the present invention relates to the use of the above cyclic peptide derivatives, or stereoisomers thereof, or non-physiologically toxic salts thereof, as MC4-R agonists.
A further aspect of the present invention relates to the use of the above cyclic peptide derivatives, or stereoisomers thereof, or non-physiologically toxic salts thereof, for the manufacture of a medicament for the treatment and/or prevention of obesity, hypertension, atherosclerosis, heart disease, or type II diabetes.
A further aspect of the present invention relates to the use of a cyclic peptide derivative as described above, or a stereoisomer thereof, or a physiologically non-toxic salt thereof, for the manufacture of a medicament for the treatment and/or prevention of sexual dysfunction.
A further aspect of the present invention relates to a method for the treatment or co-treatment and/or prevention of sexual dysfunction in a mammal, including a human, comprising administering an effective amount of a cyclic peptide derivative of the present invention, or a stereoisomer thereof, or a physiologically nontoxic salt thereof, or a pharmaceutical composition of the present invention.
Yet another aspect of the present invention relates to a method for the treatment or co-treatment and/or prevention of obesity, hypertension, atherosclerosis, heart disease, or type II diabetes in a mammal (including a human) comprising administering an effective amount of a cyclic peptide derivative of the present invention, or a stereoisomer thereof, or a physiologically nontoxic salt thereof, or a pharmaceutical composition of the present invention.
The actual dosage levels of each active ingredient in the pharmaceutical compositions of this invention can be varied so that the resulting amount of active compound is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration. Dosage levels will be selected with regard to the activity of the particular compound, the route of administration, the severity of the condition being treated and the condition and prior medical history of the patient being treated. However, it is common practice in the art to start doses of the compounds at levels below those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
The word "effective amount" of a compound of the present invention refers to a sufficient amount of the compound to treat a disorder at a reasonable benefit/risk ratio applicable to any medical treatment and/or prevention. It will be appreciated, however, that the total daily amount of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. For any particular patient, the specific therapeutically effective dose level will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the particular compound employed; the specific composition employed; the age, weight, general health, sex, and diet of the patient; the time of administration, route of administration, and rate of excretion of the particular compound employed; the duration of treatment; drugs used in combination or concomitantly with the specific compound employed; and similar factors known in the medical arts. For example, it is common in the art to start doses of the compound at levels below those required to achieve the desired therapeutic effect and to gradually increase the dose until the desired effect is achieved.
The invention is further described below.
All documents cited herein are incorporated by reference in their entirety and to the extent such documents do not conform to the meaning of the present invention, the present invention shall control. Further, the various terms and phrases used herein have the ordinary meaning as is known to those skilled in the art, and even though such terms and phrases are intended to be described or explained in greater detail herein, reference is made to the term and phrase as being inconsistent with the known meaning and meaning as is accorded to such meaning throughout this disclosure.
In the present invention, all amino acid configurations are L-form except the D-form as noted.
In the present invention, unless otherwise specified, the term "alkyl" refers to an aliphatic hydrocarbon group having from about 1 to about 15 carbon atoms in the chain, which may be straight or branched, optionally substituted with one or more halogen atoms. Particularly having from 1 to about 6 carbon atoms. Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, 3-pentyl, heptyl, octyl, nonyl, decyl, and dodecyl. Examples of alkyl groups substituted with one or more halogen atoms include trifluoromethyl. The alkyl group can also be independently selected from halogen, nitro, amino, hydroxyl, carboxyl, C by 1, 2, 3 or 41-C4Alkyl or C1-C4Alkoxy or C1-C4And (3) substituent substitution of alkylthio.
The term "alkoxy" refers to an alkyl-O-group, wherein the alkyl is as described herein. Examples of alkoxy groups include difluoromethoxy, methoxy, trifluoromethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and heptyloxy.
The term "halogen" includes fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine, bromine.
The term "cycloalkyl" refers to a saturated monocyclic or bicyclic ring system of about 3 to about 10 carbon atoms, optionally substituted with oxygen. Exemplary monocyclic cycloalkyl rings include C3-8Cycloalkyl rings, such as cyclopropyl, cyclopentyl, cyclohexyl, and cycloheptyl. Cycloalkyl may be substituted with 1, 2, 3 or 4 substituents independently selected from halogen, nitro, amino, hydroxy, carboxy, C1-C4Alkyl or C1-C4Substituent of alkoxy.
The term "aryl" is a 6-14 membered monocyclic or bicyclic aromatic group, such as phenyl or naphthyl, which is unsubstituted or independently selected from halogen, nitro, carboxy or C1-C4Alkyl substituents are mono-, di-, or tri-substituted;
the term "heteroaryl" is a 4-10 membered monocyclic or bicyclic aromatic group containing 1-5 heteroatoms independently selected from N, O and S, such as pyrrolyl, furanyl, pyridinyl and the like, which is unsubstituted or independently selected from halogen, nitro, carboxy or C1-C4Alkyl substituent mono-or di-substituted;
the term "heterocyclyl" is a non-aromatic cyclic group containing 1-5, preferably 1-3 heteroatoms independently selected from N, O and S in the ring structure, such as pyranyl, piperidinyl and the like, which is unsubstituted or independently selected from halogen, nitro, carboxy or C1-C4The substituents of the alkyl groups are mono-substituted or di-substituted or tri-substituted.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but those skilled in the art will appreciate that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
The solid phase synthesis carrier MBHA resin and PAM resin used in the embodiment are products of Tianjin Nankai synthesis responsibility limited company; DCC, HOBT, BOP, DIEA and protected natural amino acids were obtained from Gill Biochemical and Chengdu Nonow technologies, Inc. of Shanghai, and protected unnatural amino acids were provided synthetically in this laboratory, except for the description.
The abbreviations used in the present invention have the following meanings:
ac acetyl group
Aca amino caproic acid residue
Asp aspartic acid residue
Arg arginine residue
Boc tert-butyloxycarbonyl group
BOP benzotriazole-1-O-tris (dimethylamino) phosphonium hexafluorophosphate
Cpa Tetrachlorophenylalanine residue
Cys cysteine residue
DCC dicyclohexylcarbodiimide
DIEA diisopropylethylamine
Fmoc fluorenylmethyloxycarbonyl
Fpa p-fluorophenylalanine residue
hCys homocysteine residue
HOBt 1-hydroxybenzotriazole
His histidine residue
Lys lysine residue
MBHA resin phenylaminomethyl resin
alpha-MSH alpha-melanocyte stimulating hormone
Mtal 2-amino-3- (2-methylthiazolyl-4-) propionic acid residue
NAsp N-carboxyethylglycine residue
NCys N-mercaptomethylglycine residue
N-mercaptoethylglycine residues of NhCys
NLys N-aminobutylglycine residue
Nle norleucine residue
PAM resin hydroxymethyl phenylacetamide methyl resin
Phe phenylalanine residue
RP-HPLC reversed-phase high performance liquid chromatography
Tal 2-amino-3- (thiazolyl-4-) propionic acid residue
Trp Tryptophan residue
Example 1: the compound Ac-Nle-ring (Asp-His-DPhe-Arg-Trp-NLys) -NH2(1) Synthesis of (2)
Ac-Nle-loop (Asp-His-DPhe-Arg-Trp-NLys) -MBHA resin was synthesized by standard Fmoc solid phase peptide synthesis method (ref: Huang-Sheng, Chen Chang Qing, peptide Synthesis, science publishers, 1985) using 390mg of MBHA resin (0.54mmol/g) as a solid phase carrier and BOP/DIEA as a condensing agent, based on the amino acid sequence of the compound.
The peptide resin was placed in a reactor of an HF cutter, and 0.5mL of anisole and about 10mL of liquid HF were added and reacted at 0 ℃ for 40 minutes. The HF was pumped off with an oil pump, the reactor was removed, cold anhydrous ether was added to precipitate a solid, and the suspension was transferred to a sand core funnel. Washed three times with a small amount of cold anhydrous ether, eluted with 150mL of 10% aqueous acetic acid, and lyophilized to give 212mg of crude white fluffy solid peptide. Dissolving with 10% acetic acid/water 50mL, purifying by C18 reversed phase medium pressure chromatography with eluent of 20% -30% acetonitrile/1% acetic acid/water, and lyophilizing to obtain pure peptide 14.7mg, HPLC purity of 91.7%, and yield of 7%. ESI-MS: 1024.0(MW 1024).
Example 2: the compound Ac-Nle-cyclo (NAsp-His-DPhe-Arg-Trp-Lys) -NH2(2) Synthesis of (2)
Ac-Nle-loop (NAsp-His-DPhe-Arg-Trp-Lys) -MBHA resin was synthesized by standard Fmoc solid-phase peptide synthesis method (see the same example 1) using 390mg of MBHA resin (0.54mmol/g) as a solid-phase carrier and BOP/DIEA as a condensing agent, based on the amino acid sequence of the compound.
The peptide resin was placed in a reactor of an HF cutter, and 0.5mL of anisole and about 10mL of liquid HF were added and reacted at 0 ℃ for 40 minutes. The HF was pumped off with an oil pump, the reactor was removed, cold anhydrous ether was added to precipitate a solid, and the suspension was transferred to a sand core funnel. Washed three times with a small amount of cold anhydrous ether, eluted with 150mL of 10% aqueous acetic acid and lyophilized to give 196mg of crude white fluffy solid peptide. Dissolving with 10% acetic acid/water 50mL, purifying by C18 reversed phase medium pressure chromatography with eluent of 20% -30% acetonitrile/1% acetic acid/water, and lyophilizing to obtain pure peptide 10.2mg with HPLC purity of 95.4% and yield of 5%. ESI-MS: 1024.0(MW 1024).
Example 3: the compound Ac-Nle-ring (NAsp-His-DPhe-Arg-Trp-NLys) -NH2(3) Synthesis of (2)
Ac-Nle-loop (NAsp-His-DPhe-Arg-Trp-NLys) -MBHA resin was synthesized by standard Fmoc solid phase peptide synthesis method (see the same example 1) using 390mg of MBHA resin (0.54mmol/g) as a solid phase carrier and BOP/DIEA as a condensing agent, based on the amino acid sequence of the compound.
The peptide resin was placed in a reactor of an HF cutter, and 0.5mL of anisole and about 10mL of liquid HF were added and reacted at 0 ℃ for 40 minutes. The HF was pumped off with an oil pump, the reactor was removed, cold anhydrous ether was added to precipitate a solid, and the suspension was transferred to a sand core funnel. Washed three times with a small amount of cold anhydrous ether, eluted with 150mL of 10% aqueous acetic acid and lyophilized to give 196mg of crude white fluffy solid peptide. Dissolving with 10% acetic acid/water 50mL, purifying by C18 reversed phase medium pressure chromatography with eluent of 20% -30% acetonitrile/1% acetic acid/water, and lyophilizing to obtain pure peptide 10.5mg, with HPLC purity of 91.6% and yield of 5%. ESI-MS: 1024.0(MW 1024).
Example 4: the compound Ac-Nle-cyclo (Cys-His-DPhe-Arg-Trp-NhCys) -NH2(4) Synthesis of (2)
Ac-Nle-Cys-His-DPhe-Arg-Trp-NhCys-MBHA resin was synthesized by standard Fmoc solid-phase peptide synthesis method (see the same example 1) using 390mg of MBHA resin (0.54mmol/g) as a solid-phase carrier and BOP/DIEA as a condensing agent, based on the amino acid sequence of the compound.
The peptide resin is dried and then cracked by anhydrous hydrogen fluoride, and then the linear precursor crude peptide 176mg is obtained by freeze-drying, 100mL of water is added for dissolution, the pH value is adjusted to 8.4 by 10% ammonia water, and the solution turns pink slightly. Potassium ferricyanide (100 mg) was added under magnetic stirring at room temperature, and the solution became yellow. The reaction progress was monitored by HPLC and the reaction was complete in about 10 min. Adding about 10g of anion exchange resin, and stirring at room temperature for about 20min until the yellow color of the solution disappears; filtered and washed with 20mL × 2 times. The aqueous solutions are combined, and the mixture is directly subjected to medium-pressure separation, purification and freeze-drying to finally obtain 14.4mg of pure peptide with the HPLC purity of 93.5 percent and the yield of 7 percent. ESI-MS: 1017.7(MW 1017).
Example 5: the compound Ac-Nle-cyclo (NhCys-His-DPhe-Arg-Trp-Cys) -NH2(5) Synthesis of (2)
Ac-Nle-NhCys-His-DPhe-Arg-Trp-Cys-MBHA resin was synthesized by standard Fmoc solid-phase peptide synthesis method (see the same example 1) using 390mg of MBHA resin (0.54mmol/g) as a solid-phase carrier and BOP/DIEA as a condensing agent, based on the amino acid sequence of the compound.
The peptide resin is dried and then cracked by anhydrous hydrogen fluoride, and the linear precursor crude peptide 185mg is obtained by freeze-drying, dissolved by adding 100mL of water, and the pH value is adjusted to 8.4 by 10 percent ammonia water, and the solution turns pink slightly. Potassium ferricyanide (100 mg) was added under magnetic stirring at room temperature, and the solution became yellow. The reaction progress was monitored by HPLC and the reaction was complete in about 10 min. Adding about 10g of anion exchange resin, and stirring at room temperature for about 20min until the yellow color of the solution disappears; filtered and washed with 20mL × 2 times. Mixing the water solutions, directly performing medium pressure separation and purification, and lyophilizing to obtain 16.1mg of pure peptide with HPLC purity of 96.2% and yield of 8%. ESI-MS: 1017.6(MW 1017).
Example 6: the compound Ac-Nle-cyclo (Cys-His-DCpa-Arg-Trp-NhCys) -NH2(10) Synthesis of (2)
Ac-Nle-Cys-His-DCpa-Arg-Trp-NhCys-MBHA resin was synthesized by standard Fmoc solid-phase peptide synthesis method (see the same example 1) using 390mg of MBHA resin (0.54mmol/g) as a solid-phase carrier and BOP/DIEA as a condensing agent, based on the amino acid sequence of the compound.
The peptide resin is dried and then cracked by anhydrous hydrogen fluoride, the crude peptide of the linear precursor 192mg is obtained by freeze-drying, 100mL of water is added for dissolution, the pH value is adjusted to 8.4 by 10 percent ammonia water, and the solution turns pink slightly. Potassium ferricyanide (100 mg) was added under magnetic stirring at room temperature, and the solution became yellow. The reaction progress was monitored by HPLC and the reaction was complete in about 10 min. Adding about 10g of anion exchange resin, and stirring at room temperature for about 20min until the yellow color of the solution disappears; filtered and washed with 20mL × 2 times. The aqueous solutions are combined, and the mixture is directly subjected to medium-pressure separation, purification and freeze-drying to finally obtain 11.1mg of pure peptide, the HPLC purity is 94.2 percent, and the yield is 5 percent. ESI-MS: 1050.8(MW 1051).
Example 7: compound Biotin-Nle-ring (Asp-His-DPhe-Arg-Trp-Lys) -NH2(25) Synthesis of (2)
Biotin-Nle-ring (Asp-His-DPhe-Arg-Trp-Lys) -MBHA resin was synthesized by standard Fmoc solid-phase peptide synthesis method (see the same reference as example 1) using 390mg of MBHA resin (0.54mmol/g) as a solid-phase carrier and BOP/DIEA as a condensing agent, based on the amino acid sequence of the compound.
The peptide resin was placed in a reactor of an HF cutter, and 0.5mL of anisole and about 10mL of liquid HF were added and reacted at 0 ℃ for 40 minutes. The HF was pumped off with an oil pump, the reactor was removed, cold anhydrous ether was added to precipitate a solid, and the suspension was transferred to a sand core funnel. Washed three times with a small amount of cold anhydrous ether, and then eluted with 150mL of 10% aqueous acetic acid to give crude peptide as a white fluffy solid after freeze-drying, 210 mg. Dissolving with 10% acetic acid/water 50mL, purifying by C18 reversed phase medium pressure chromatography with eluent of 20% -30% acetonitrile/1% acetic acid/water, and lyophilizing to obtain pure peptide 12.7mg with HPLC purity of 94.8% and yield of 5%. ESI-MS: 1208.0(MW 1208).
Example 8: the compound Ac-Nle-cyclo (Cys-Tal-DPhe-Arg-Trp-NhCys) -NH2(38) Synthesis of (2)
Ac-Nle-Cys-Tal-DPhe-Arg-Trp-NhCys-MBHA resin was synthesized by standard Fmoc solid phase peptide synthesis method (see the same example 1) using 390mg of MBHA resin (0.54mmol/g) as a solid phase carrier and BOP/DIEA as a condensing agent, based on the amino acid sequence of the compound.
The peptide resin is dried and then cracked by anhydrous hydrogen fluoride, and freeze-dried to obtain 201mg of linear precursor crude peptide, 100mL of water is added for dissolution, the pH value is adjusted to 8.4 by 10% ammonia water, and the solution is slightly pink. Potassium ferricyanide (100 mg) was added under magnetic stirring at room temperature, and the solution became yellow. The reaction progress was monitored by HPLC and the reaction was complete in about 10 min. Adding about 10g of anion exchange resin, and stirring at room temperature for about 20min until the yellow color of the solution disappears; filtered and washed with 20mL × 2 times. Mixing the water solutions, directly performing medium pressure separation and purification, and lyophilizing to obtain pure peptide 12.4mg with HPLC purity of 95.6% and yield of 6%. ESI-MS: 1033.8(MW 1034).
Example 9: the compound Ac-Aca-cyclo (NAsp-His-DPhe-Arg-Trp-NLys) -NH2(71) Synthesis of (2)
Biotin-Nle-ring (Asp-His-DCpa-Arg-Trp-Lys) -MBHA resin was synthesized by standard Fmoc solid-phase peptide synthesis method (see the same reference as example 1) using 390mg of MBHA resin (0.54mmol/g) as a solid-phase carrier and BOP/DIEA as a condensing agent, based on the amino acid sequence of the compound.
The peptide resin was placed in a reactor of an HF cutter, and 0.5mL of anisole and about 10mL of liquid HF were added and reacted at 0 ℃ for 40 minutes. The HF was pumped off with an oil pump, the reactor was removed, cold anhydrous ether was added to precipitate a solid, and the suspension was transferred to a sand core funnel. Washed three times with a small amount of cold anhydrous ether, and then eluted with 150mL of 10% aqueous acetic acid to give crude peptide as a white fluffy solid after freeze-drying, 210 mg. Dissolving with 10% acetic acid/water 50mL, purifying by C18 reversed phase medium pressure chromatography with eluent of 20% -30% acetonitrile/1% acetic acid/water, and lyophilizing to obtain pure peptide 15.7mg with HPLC purity of 92.1% and yield of 6%. ESI-MS: 1023.9(MW 1024).
Example 10: the compound Ac-Aca-cyclo (Cys-His-DPhe-Arg-Trp-NhCys) -NH2(72) And (4) synthesizing.
Ac-Aca-Cys-His-DPhe-Arg-Trp-NhCys-MBHA resin was synthesized by standard Fmoc solid-phase peptide synthesis method (see the same example 1) using 390mg of MBHA resin (0.54mmol/g) as a solid-phase carrier and BOP/DIEA as a condensing agent, based on the amino acid sequence of the compound.
The peptide resin is dried and then cracked by anhydrous hydrogen fluoride, and freeze-dried to obtain 201mg of linear precursor crude peptide, 100mL of water is added for dissolution, the pH value is adjusted to 8.4 by 10% ammonia water, and the solution is slightly pink. Potassium ferricyanide (100 mg) was added under magnetic stirring at room temperature, and the solution became yellow. The reaction progress was monitored by HPLC and the reaction was complete in about 10 min. Adding about 10g of anion exchange resin, and stirring at room temperature for about 20min until the yellow color of the solution disappears; filtered and washed with 20mL × 2 times. The aqueous solutions are combined, and medium-pressure separation, purification and freeze-drying are directly carried out, so that 15.1mg of pure peptide is finally obtained, the HPLC purity is 93.6%, and the yield is 7%. ESI-MS: 1016.7(MW 1017).
Example 11: the compound Ac-Aca-cyclo (NhCys-His-DPhe-Arg-Trp-Cys) -NH2(73) And (4) synthesizing.
Ac-Aca-NhCys-His-DPhe-Arg-Trp-Cys-MBHA resin was synthesized by standard Fmoc solid-phase peptide synthesis method (see the same example 1) using 390mg of MBHA resin (0.54mmol/g) as a solid-phase carrier and BOP/DIEA as a condensing agent, based on the amino acid sequence of the compound.
The peptide resin is dried and then cracked by anhydrous hydrogen fluoride, the crude peptide of the linear precursor 192mg is obtained by freeze-drying, 100mL of water is added for dissolution, the pH value is adjusted to 8.4 by 10 percent ammonia water, and the solution turns pink slightly. Potassium ferricyanide (100 mg) was added under magnetic stirring at room temperature, and the solution became yellow. The reaction progress was monitored by HPLC and the reaction was complete in about 10 min. Adding about 10g of anion exchange resin, and stirring at room temperature for about 20min until the yellow color of the solution disappears; filtered and washed with 20mL × 2 times. Mixing the water solutions, directly performing medium pressure separation and purification, and lyophilizing to obtain pure peptide 15.6mg with HPLC purity of 94.8% and yield of 7%. ESI-MS: 1016.9(MW 1017).
Example 12: the compound Ac-Aca-cyclo (Cys-His-DCpa-Arg-Trp-NhCys) -NH2(78) Synthesis of (2)
Ac-Aca-Cys-His-DCpa-Arg-Trp-NhCys-MBHA resin was synthesized by standard Fmoc solid-phase peptide synthesis method (see the same example 1) using 390mg of MBHA resin (0.54mmol/g) as a solid-phase carrier and BOP/DIEA as a condensing agent, based on the amino acid sequence of the compound.
The peptide resin is dried and then cracked by anhydrous hydrogen fluoride, and the linear precursor crude peptide 185mg is obtained by freeze-drying, dissolved by adding 100mL of water, and the pH value is adjusted to 8.4 by 10 percent ammonia water, and the solution turns pink slightly. Potassium ferricyanide (100 mg) was added under magnetic stirring at room temperature, and the solution became yellow. The reaction progress was monitored by HPLC and the reaction was complete in about 10 min. Adding about 10g of anion exchange resin, and stirring at room temperature for about 20min until the yellow color of the solution disappears; filtered and washed with 20mL × 2 times. Mixing the water solutions, directly performing medium pressure separation and purification, and lyophilizing to obtain pure peptide 10.8mg with HPLC purity of 94.8% and yield of 5%. ESI-MS: 1051.7(MW 1051).
Example 13: the compound Ac-Aca-cyclo (Cys-Tal-DPhe-Arg-Trp-NhCys) -NH2(106) Synthesis of (2)
Ac-Aca-Cys-Tal-DPhe-Arg-Trp-NhCys-MBHA resin was synthesized by standard Fmoc solid phase peptide synthesis method (see the same example 1) using 390mg of MBHA resin (0.54mmol/g) as a solid phase carrier and BOP/DIEA as a condensing agent, based on the amino acid sequence of the compound.
The peptide resin is dried and then cracked by anhydrous hydrogen fluoride, and the linear precursor crude peptide 185mg is obtained by freeze-drying, dissolved by adding 100mL of water, and the pH value is adjusted to 8.4 by 10 percent ammonia water, and the solution turns pink slightly. Potassium ferricyanide (100 mg) was added under magnetic stirring at room temperature, and the solution became yellow. The reaction progress was monitored by HPLC and the reaction was complete in about 10 min. Adding about 10g of anion exchange resin, and stirring at room temperature for about 20min until the yellow color of the solution disappears; filtered and washed with 20mL × 2 times. Mixing the water solutions, directly performing medium pressure separation and purification, and lyophilizing to obtain pure peptide 10.5mg with HPLC purity of 97.1% and yield of 5%. ESI-MS: 1034.9(MW 1035).
Example 14: the compound Ac-Aca-cyclo (Cys-Tal-DCpa-Arg-Trp-NhCys) -NH2(112) Synthesis of (2)
Ac-Aca-Cys-Tal-DCpa-Arg-Trp-NhCys-MBHA resin was synthesized by standard Fmoc solid-phase peptide synthesis method (see the same example 1) using 390mg of MBHA resin (0.54mmol/g) as a solid-phase carrier and BOP/DIEA as a condensing agent, based on the amino acid sequence of the compound.
The peptide resin is dried and then cracked by anhydrous hydrogen fluoride, the linear precursor crude peptide 207mg is obtained by freeze-drying, 100mL of water is added for dissolution, the pH value is adjusted to 8.4 by 10 percent ammonia water, and the solution is slightly pink. Potassium ferricyanide (100 mg) was added under magnetic stirring at room temperature, and the solution became yellow. The reaction progress was monitored by HPLC and the reaction was complete in about 10 min. Adding about 10g of anion exchange resin, and stirring at room temperature for about 20min until the yellow color of the solution disappears; filtered and washed with 20mL × 2 times. Mixing the water solutions, directly performing medium pressure separation and purification, and lyophilizing to obtain 13.7mg of pure peptide with HPLC purity of 96.4% and yield of 6%. ESI-MS: 1067.8(MW 1068).
Example 15: test for evaluating receptor binding Activity
The experimental method comprises the following steps: radioligand receptor binding assays
Materials: membrane protein rich in MC4-R extracted from rat brain tissue; [125I]NDP-. alpha. -MSH, Perkinelmer.
The experimental principle is as follows: the characteristics of high affinity, specificity, saturation and reversibility of the combination of the receptor and the ligand and high sensitivity of radionuclide measurement are utilized to ensure that the receptor and the labeled ligand thereof are combined under certain conditions, the reaction is stopped when the reaction reaches the equilibrium or at different time points, the free labeled ligand and the labeled ligand which is combined with the receptor specificity are separated, the radioactivity of the free labeled ligand and the labeled ligand which are combined with the receptor specificity are respectively measured, and the concentration of the radioactive labeled ligand and the labeled ligand is calculated.
And (3) calculating indexes: percent binding inhibition, percent binding inhibition ═ (competitive binding-non-specific binding)/(total binding-non-specific binding) × 100%.
A higher percentage of inhibition of binding indicates a higher binding activity of the compound to the receptor.
Compound screening: two concentrations of 10nM and 100nM were chosen, with PT-141 as a positive control, and each test sample was replicated 3 times. Table 1 gives the results for the compounds with higher inhibition. It can be seen that at 100nM level, there are 11 compounds that inhibit 50%; at 10nM level, 5 compounds inhibited 50%, comparable to the positive control PT-141, showing higher receptor binding activity.
TABLE 1 evaluation results of receptor binding Activity
Although specific embodiments of the invention have been described in detail, those skilled in the art will appreciate. Various modifications and substitutions of those details may be made in light of the overall teachings of the disclosure, and such changes are intended to be within the scope of the present invention. The full scope of the invention is given by the appended claims and any equivalents thereof.
Claims (5)
1. A cyclopeptide derivative, or a stereoisomer thereof, or a physiologically nontoxic salt thereof, wherein the cyclopeptide derivative is selected from the group consisting of:
(10) Ac-Nle-cyclo (Cys-His-DCpa-Arg-Trp-NhCys) -NH2And are and
(78) Ac-Aca-cyclo (Cys-His-DCpa-Arg-Trp-NhCys) -NH2。
2. A pharmaceutical composition comprising the cyclic peptide derivative of claim 1, or a stereoisomer thereof, or a physiologically nontoxic salt thereof, and a pharmaceutically acceptable carrier or adjuvant.
3. Use of a cyclic peptide derivative of claim 1, or a stereoisomer thereof, or a physiologically nontoxic salt thereof, as an MC4-R agonist.
4. Use of a cyclic peptide derivative according to claim 1, or a stereoisomer thereof, or a physiologically nontoxic salt thereof, for the manufacture of a medicament for the treatment and/or prevention of obesity.
5. Use of a cyclic peptide derivative according to claim 1, or a stereoisomer thereof, or a physiologically nontoxic salt thereof, for the manufacture of a medicament for the treatment and/or prevention of sexual dysfunction.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010196955.0A CN102276698B (en) | 2010-06-10 | 2010-06-10 | MC4-R cyclopeptide agonist and application thereof |
| PCT/CN2011/000761 WO2011153817A1 (en) | 2010-06-10 | 2011-04-29 | Cyclopeptides used as melanocortin-4 receptor agonist |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010196955.0A CN102276698B (en) | 2010-06-10 | 2010-06-10 | MC4-R cyclopeptide agonist and application thereof |
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| CN102276698A CN102276698A (en) | 2011-12-14 |
| CN102276698B true CN102276698B (en) | 2014-02-26 |
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| CN201010196955.0A Expired - Fee Related CN102276698B (en) | 2010-06-10 | 2010-06-10 | MC4-R cyclopeptide agonist and application thereof |
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| WO (1) | WO2011153817A1 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US10899793B2 (en) | 2016-05-27 | 2021-01-26 | Regents Of The University Of Minnesota | Melanocortin ligands and methods of use thereof |
| US11124541B2 (en) | 2016-10-18 | 2021-09-21 | Regents Of The University Of Minnesota | Chimeric melanocortin ligands and methods of use thereof |
| US11332499B2 (en) | 2018-08-16 | 2022-05-17 | Regents Of The University Of Minnesota | Cyclic peptides and methods of use thereof |
| CN110981936B (en) * | 2018-09-28 | 2021-10-12 | 北京京东方技术开发有限公司 | Peptoid compound, preparation method thereof, oligomer, pharmaceutical composition and kit |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1415596A (en) * | 2001-11-02 | 2003-05-07 | 中国人民解放军军事医学科学院毒物药物研究所 | Amine derivative possessing the function of anti-pulmonary hypertension and its application in pharmacological science |
| EP1593384A2 (en) * | 1999-06-29 | 2005-11-09 | Palatin Technologies, Inc. | Compositions for treatment of sexual dysfunction |
| WO2007123839A2 (en) * | 2006-04-18 | 2007-11-01 | University Of Florida Research Foundation, Inc. | Peptides with efficacy in rescuing melanocortin-4 receptor polymorphic agonist signaling |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5731408A (en) * | 1995-04-10 | 1998-03-24 | Arizona Board Of Regents On Behalf Of The University Of Arizona | Peptides having potent antagonist and agonist bioactivities at melanocortin receptors |
| CN1809372A (en) * | 2003-06-19 | 2006-07-26 | 伊莱利利公司 | Melanocortin recptor 4(MC4) agonists and their uses |
| RU2381233C2 (en) * | 2003-09-30 | 2010-02-10 | Ново Нордиск А/С | Melanocortin receptor agonists |
| EP1809667A1 (en) * | 2004-11-04 | 2007-07-25 | Novo Nordisk A/S | Peptides for use in the treatment of obesity |
| US20090081197A1 (en) * | 2007-06-01 | 2009-03-26 | Palatin Technologies, Inc. | Methods for Selection of Melanocortin Receptor-Specific Agents for Treatment of Obesity |
-
2010
- 2010-06-10 CN CN201010196955.0A patent/CN102276698B/en not_active Expired - Fee Related
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2011
- 2011-04-29 WO PCT/CN2011/000761 patent/WO2011153817A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1593384A2 (en) * | 1999-06-29 | 2005-11-09 | Palatin Technologies, Inc. | Compositions for treatment of sexual dysfunction |
| CN1415596A (en) * | 2001-11-02 | 2003-05-07 | 中国人民解放军军事医学科学院毒物药物研究所 | Amine derivative possessing the function of anti-pulmonary hypertension and its application in pharmacological science |
| WO2007123839A2 (en) * | 2006-04-18 | 2007-11-01 | University Of Florida Research Foundation, Inc. | Peptides with efficacy in rescuing melanocortin-4 receptor polymorphic agonist signaling |
Non-Patent Citations (2)
| Title |
|---|
| Boman G. Irani, et.al.Progress in the Development of Melanocortin Receptor Selective Ligands.《Current Pharmaceutical Design》.2004,第10卷(第28期), |
| Progress in the Development of Melanocortin Receptor Selective Ligands;Boman G. Irani, et.al;《Current Pharmaceutical Design》;20041130;第10卷(第28期);摘要、第3450页表1、第3454左栏倒数第1段-右栏第2段、第3461页左栏倒数第1段-第3462页右栏第2段、第3462页右栏倒数第1段、3464页左栏第2段 * |
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| Publication number | Publication date |
|---|---|
| WO2011153817A1 (en) | 2011-12-15 |
| CN102276698A (en) | 2011-12-14 |
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