公开(公告)号：US5245009A

公开(公告)日：1993-09-14

申请号：US715752

申请日：1991-06-14

申请人： Wayne D. Kornreich ,  Jean-Francois Hernandez ,  Jean E. F. Rivier ,  Catherine L. Rivier ,  Wylie W. Vale, Jr.

发明人： Wayne D. Kornreich ,  Jean-Francois Hernandez ,  Jean E. F. Rivier ,  Catherine L. Rivier ,  Wylie W. Vale, Jr.

IPC分类号： A61K38/00 ,  C07K14/575

CPC分类号： C07K14/57509 ,  A61K38/00 ,  Y10S930/26

摘要： Disclosed are improved CRF peptide antagonists such as those having the formula: Y-D-Phe-R.sub.13 -Leu-Leu-Arg-R.sub.17 -R.sub.18 -Leu-R.sub.20 -Nle-R.sub.22 -R.sub.23 -R.sub.24 -R.sub.25 -R.sub.26 -Leu-R.sub.28 -R.sub.29 -Gln-R.sub.31 -R.sub.32 -R.sub.33 -R.sub.34 -Arg-R.sub.36 -R.sub.37 -Nle-R.sub.39 -R.sub.40 -R.sub.41 -NH.sub.2 wherein Y is Ac or hydrogen; R.sub.13 is His, Tyr or Glu; R.sub.17 is Cys, Glu, Asn or Lys; R.sub.18 is Val, Nle or Met; R.sub.20 is D-Cys, Glu, D-Glu, Aib or D-Ala; R.sub.22 is Ala, Aib, Thr, Asp or Glu; R.sub.23 is Arg, Orn, Har or Lys; R.sub.24 is Ala or Aib; R.sub.25 is Asp or Glu; R.sub.26 is Gln, Asn or Lys; R.sub.28 is Ala or Aib; R.sub.29 is Gln, Aib or Glu, R.sub.31 is Ala or Aib; R.sub.32 is His, Aib, Gly, Tyr or Ala; R.sub.33 is Ser, Aib, Asn, Leu, Thr or Ala; R.sub.34 is Asn or Aib; R.sub.36 is Lys, Orn, Arg, Har or Leu; R.sub.37 is Leu or Try; R.sub.39 is Glu, Aib or Asp; R.sub.40 is Ile, Aib, Thr, Glu, Ala, Val, Leu, Nle, Phe, Nva, Gly or Gln; and R.sub.41 is Ala, Ile, Gly, Val, Leu, Nle, Phe, Nva or Gln. Specific CRF antagonists disclosed include [D-Phe.sup.12, D-Ala.sup.20, Nle.sup.21,38,]-rCRF(12-41), [D-Phe.sup.12, Nle.sup.21,38, Aib.sup.33 ]-rCRF(12-41) and (c 17-20) [D-Phe.sup.12, Cys.sup.17, D-Cys.sup.20, Nle.sup.21,38 ]-rCRF(12-41).

摘要翻译： 公开了改进的CRF肽拮抗剂，例如具有下式的那些：肽，如YD-Phe-R13-Leu-Leu-Arg-R17-R18-Leu-R20-Nle-R22-R23-R24-R25-R26-Leu-R2 8- R29-Gln-R31-R32-R33-R34-Arg-R36-R37-Nle-R39-R40-R41-NH2，其中Y是Ac或氢; R13是His，Tyr或Glu; R17是Cys，Glu，Asn或Lys; R18为Val，Nle或Met; R20是D-Cys，Glu，D-Glu，Aib或D-Ala; R22是Ala，Aib，Thr，Asp或Glu; R23是Arg，Orn，Har或Lys; R24是Ala或Aib; R25为Asp或Glu; R26是Gln，Asn或Lys; R28是Ala或Aib; R29是Gln，Aib或Glu，R31是Ala或Aib; R32是His，Aib，Gly，Tyr或Ala; R33是Ser，Aib，Asn，Leu，Thr或Ala; R34是Asn或Aib; R36是Lys，Orn，Arg，Har或Leu; R37是Leu或Try; R39是Glu，Aib或Asp; R40是Ile，Aib，Thr，Glu，Ala，Val，Leu，Nle，Phe，Nva，Gly或Gln; R41是Ala，Ile，Gly，Val，Leu，Nle，Phe，Nva或Gln。 公开的具体的CRF拮抗剂包括[D-Phe12，D-Ala20，Nle21,38] -rCRF（12-41），[D-Phe12，Nle21,38，Aib33] -rCRF（12-41）和（c17- 20）[D-Phe12，Cys17，D-Cys20，Nle21,38] -rCRF（12-41）。

公开(公告)号：US5235036A

公开(公告)日：1993-08-10

申请号：US709091

申请日：1991-05-31

申请人： Wayne D. Kornreich ,  Jean-Francois Hernandez ,  Jean E. F. Rivier ,  Wylie W. Vale, Jr.

发明人： Wayne D. Kornreich ,  Jean-Francois Hernandez ,  Jean E. F. Rivier ,  Wylie W. Vale, Jr.

IPC分类号： A61K38/00 ,  C07K14/575

CPC分类号： C07K14/57509 ,  A61K38/00 ,  Y10S930/26

摘要： Analogs of CRF, which are based upon hCRF, oCRF and alpha-helical CRF, are disclosed that can be administered to achieve a substantial elevation of ACTH, .beta.-endorphin, .beta.-lipotropin, other products of the pro-opiomelanocortin gene and corticosterone levels. Analogs include those having the formula: Y-R.sub.1 -R.sub.2 -R.sub.3 -R.sub.4 -R.sub.5 -Ile-Ser-Leu-Asp-Leu-Thr-Phe-His-Leu-Leu-Arg-Glu-Val-Leu-R.sub.20 -R.sub.21 -R.sub.22 -R.sub.23 -R.sub.24 -R.sub.25 -Gln-Leu-Ala-Gln-Gln-Ala-R.sub.32 -Ser-Asn-Arg-Lys-Leu-R.sub.38 -R.sub.39 -Ile-R.sub.41 -NH.sub.2, wherein Y is an acyl group having 7 or fewer carbon atoms or hydrogen; R.sub.1 is Ser or desR.sub.1 ; R.sub.2 is Glu, Gln or desR.sub.2 ; R.sub.3 is Glu or desR.sub.3 ; R.sub.4 is Pro or desR.sub.4 ; R.sub.5 is Pro or desR.sub.5 ; R.sub.20 is Ala or Glu; R.sub.21 is Met or Nle; R.sub.22 is Ala or Thr; R.sub.23 is Arg or Lys; R.sub.24 is D-Ala or Ala; R.sub.25 is Glu or Asp; R.sub.32 is D-His or His; R.sub.38 is Met, Nle or Leu; R.sub.39 is Ala, Glu or Asp; R.sub.41 is Ile or Ala; provided however that at least one of R.sub.20 and R.sub.39 is Ala. One example is [Ala.sup.20 ]-oCRF. These analogs or their pharmaceutically acceptable salts, dispersed in an acceptable liquid or solid carrier, can be administered to humans.

公开(公告)号：US5098995A

公开(公告)日：1992-03-24

申请号：US342751

申请日：1989-04-25

申请人： Jean E. F. Rivier ,  Wylie W. Vale, Jr. ,  Catherine L. Rivier

发明人： Jean E. F. Rivier ,  Wylie W. Vale, Jr. ,  Catherine L. Rivier

IPC分类号： A61K38/04 ,  A61K38/00 ,  A61P5/00 ,  C07K14/575 ,  C07K14/60

CPC分类号： C07K14/60 ,  A61K38/00

摘要： The invention provides synthetic peptides which are extremely potent in stimulating the release of pituitary GH in animals, including humans and also resist enzymatic degradation in the body. The peptides have the sequence: (B)R.sub.1 -R.sub.2 -R.sub.3 -Ala-(Q.sub.1)R.sub.5 -Phe-Thr-R.sub.8 -Ser(Q.sub.2)R.sub.10 -Arg-R.sub.12 -(Q.sub.3)R.sub.13 -Leu-R.sub.15 -Gln-(Q.sub.4)Leu-R.sub.18 -(Q.sub.5)Ala-Arg-R.sub.21 -(Q.sub.6)R.sub.22 -(Q.sub.7)Leu-R.sub.24 -R.sub.25 -(Q.sub.8)R.sub.26 -(Q.sub.9)R.sub.27 -R.sub.28 -Arg-Gln-Gln-Gly-Glu-R.sub.34 -Asn-Gln-Glu-R.sub.38 -R.sub.39 -R.sub.40 -Arg-R.sub.42 -R.sub.43 -R.sub.44 wherein R.sub.1 is Tyr, D-Tyr, Met, Phe, D-Phe, pCl-Phe, Leu, His or D-His; B is H, C.sup.a Me, N.sup.a Me, desamino, Ac or For; R.sub.2 is Ala, D-Ala, NMA or D-NMA; R.sub.3 is Asp or D-Asp; R.sub.5 is Ile or Leu; R.sub.8 is Ser, Asn, Lys, Arg, Asp or Glu; R.sub.10 is Tyr, D-Tyr or Phe; R.sub.12 is Arg or Lys; R.sub.13 is Ile, Val, Leu or Ala; R.sub.15 is Gly or Ala; R.sub.18 is Ser or Tyr; R.sub.21 is Lys, D-Lys, Arg or D-Arg; R.sub.22 is Leu, Ile, Ala or Val; R.sub.24 is Gln or His; R.sub.25 is Asp or Glu; R.sub.26 is Ile or Leu; R.sub.27 is Met, D-Met, Ala, Nle, Ile, Leu, Nva or Val; R.sub.28 is Asn or Ser; R.sub.34 is Ser or Arg; R.sub.38 is Arg or Gln; R.sub.39 is Gly or Arg; R.sub.40 is Ala or Ser; R.sub.42 is Phe, Ala or Val; R.sub.43 is Asn or Arg; R.sub.44 is a natural amino acid; Q.sub.1 -Q.sub.9 are either H or C.sup.a Me, provided however that one of Q.sub.1 -Q.sub.9 is C.sup.a Me. These peptides may also be used diagnostically, and the C-terminus can be shortened to residue-29.

摘要翻译： 本发明提供了合成肽，其在刺激包括人在内的动物中垂体GH的释放方面非常有效，并且还抵抗体内的酶降解。 肽具有以下顺序：（B）R1-R2-R3-Ala-（Q1）R5-Phe-Thr-R8-Ser（Q2）R10-Arg-R12-（Q3）R13-Leu-R15-Gn- （Q4）Leu-R18-（Q5）Ala-Arg-R21-（Q6）R22-（Q7）Leu-R24-R25-（Q8）R26-（Q9）R27-R28-Arg-Gln-Gln-Gly- Glu-R34-Asn-Gln-Glu-R38-R39-R40-Arg-R42-R43-R44其中R1是Tyr，D-Tyr，Met，Phe，D-Phe，pCl-Phe，Leu，His或D- 他的 B是H，CaMe，NaMe，desamino，Ac或For; R2是Ala，D-Ala，NMA或D-NMA; R3是Asp或D-Asp; R5是Ile或Leu; R8是Ser，Asn，Lys，Arg，Asp或Glu; R10是Tyr，D-Tyr或Phe; R12是Arg或Lys; R13是Ile，Val，Leu或Ala; R15是Gly或Ala; R18为Ser或Tyr; R21为Lys，D-Lys，Arg或D-Arg; R22是Leu，Ile，Ala或Val; R24是Gln或His; R25为Asp或Glu; R26是Ile或Leu; R27是Met，D-Met，Ala，Nle，Ile，Leu，Nva或Val; R28为Asn或Ser; R34是Ser或Arg; R38是Arg或Gln; R39为Gly或Arg; R40是Ala或Ser; R42是Phe，Ala或Val; R43是Asn或Arg; R44是天然氨基酸; Q1-Q9是H或CaMe，但Q1-Q9中的一个是CaMe。 这些肽也可以在诊断上使用，并且C末端可以缩短为残基29。

公开(公告)号：US4740500A

公开(公告)日：1988-04-26

申请号：US946454

申请日：1986-12-23

申请人： Wylie W. Vale, Jr. ,  Jean E. F. Rivier

发明人： Wylie W. Vale, Jr. ,  Jean E. F. Rivier

IPC分类号： A61K38/00 ,  C07K7/23 ,  A61K37/43 ,  C07K7/20

CPC分类号： C07K7/23 ,  A61K38/00 ,  Y10S514/80 ,  Y10S930/13

摘要： Peptides which inhibit the secretion of gonadotropins by the pituitary gland and inhibit the release of steroids by the gonads. Administration of an effective amount prevents ovulation of female mammalian eggs and/or the release of steroids by the gonads. The peptides have the structure: Ac-.beta.-D-NAL-R.sub.2 -D-3PAL-Ser-Arg-R.sub.6 -Leu-Arg-Pro-R.sub.10 wherein R.sub.2 is Cl-D-Phe, F-D-Phe, NO.sub.2 -D-Phe, Br-D-Phe, 3,4Cl.sub.2 -D-Phe or C.alpha.Me-Cl-D-Phe; R.sub.6 is D-3PAL, D-Trp, For-D-Trp, NO.sub.2 -D-Trp, (imBzl)D-His, D-Tyr or .beta.-D-NAL; and R.sub.10 is Gly-NH.sub.2, NHCH.sub.2 CH.sub.3, NHNHCONH.sub.2 or D-Ala-NH.sub.2.

摘要翻译： 抑制垂体分泌促性腺激素并抑制性腺释放类固醇的肽。 施用有效量防止雌性哺乳动物卵的排卵和/或性腺释放类固醇。 肽具有以下结构：Ac-β-D-NAL-R2-D-3PAL-Ser-Arg-R6-Leu-Arg-Pro-R10，其中R2是Cl-D-Phe，FD-Phe， Phe，Br-D-Phe，3,4Cl2-D-Phe或CαMe-Cl-D-Phe; R6是D-3PAL，D-Trp，For-D-Trp，NO2-D-Trp，（imBz1）D-His，D-Tyr或β-D-NAL; 并且R 10是Gly-NH 2，NHCH 2 CH 3，NHNHCONH 2或D-Ala-NH 2。

公开(公告)号：US4652550A

公开(公告)日：1987-03-24

申请号：US653867

申请日：1984-09-21

申请人： Jean E. F. Rivier ,  Wylie W. Vale, Jr.

发明人： Jean E. F. Rivier ,  Wylie W. Vale, Jr.

IPC分类号： A61K38/00 ,  C07K7/23 ,  A61K37/43 ,  C07K7/20

CPC分类号： C07K7/23 ,  A61K38/00 ,  Y10S514/80 ,  Y10S930/13

摘要： Peptides which inhibit the secretion of gonadotropins by the pituitary gland and inhibit the release of steroids by the gonads. Administration of an effective amount prevents ovulation of female mammalian eggs and/or the release of steroids by the gonads. The peptides have the structure: X-R.sub.1 -R.sub.2 -R.sub.3 -Ser-Tyr-R.sub.6 -R.sub.7 -Arg-Pro-R.sub.10 wherein X is hydrogen or an acyl group having 7 or less carbon atoms; R.sub.1 is dehydro-Pro or .beta.-D-NAL; R.sub.2 is Cl-D-Phe, F-D-Phe, NO.sub.2 -D-Phe, C.sup..alpha. Me-4-Cl-D-Phe, Cl.sub.2 -D-Phe or Br-D-Phe; R.sub.3 is D-Trp, substituted D-Trp, .beta.-D-NAL, or D-PAL; R.sub.6 is a D-isomer of a lipophilic amino acid or is 4-NH.sub.2 -D-Phe, D-Lys, D-Orn, D-Har, D-His, 4-gua-D-Phe, D-PAL or D-Arg; R.sub.7 is Nle, Phe, Met, Tyr, Nva, Trp, Cys, PAL or 4F-D-Phe; and R.sub.10 is Gly-NH.sub.2 or D-Ala-NH.sub.2 ; provided however that when R.sub.1 is .beta.-D-NAL, then R.sub.6 is 4-NH.sub.2 -D-Phe, D-Lys, D-Orn, D-Har, D-His, 4-gua-D-Phe, D-PAL or D-Arg.

摘要翻译： 抑制垂体分泌促性腺激素并抑制性腺释放类固醇的肽。 施用有效量防止雌性哺乳动物卵的排卵和/或性腺释放类固醇。 肽具有以下结构：X-R1-R2-R3-Ser-Tyr-R6-R7-Arg-Pro-R10，其中X是氢或具有7个或更少碳原子的酰基; R1是脱氢-Pro或β-D-NAL; R2是Cl-D-Phe，F-D-Phe，NO2-D-Phe，CαMe-4-Cl-D-Phe，Cl2-D-Phe或Br-D-Phe; R3是D-Trp，取代的D-Trp，β-D-NAL或D-PAL; R6是亲脂性氨基酸的D-异构体，或者是4-NH2-D-Phe，D-Lys，D-Orn，D-Har，D-His，4-胍-D-Phe，D-PAL或D g R7是Nle，Phe，Met，Tyr，Nva，Trp，Cys，PAL或4F-D-Phe; 而R10为Gly-NH2或D-Ala-NH2; 但是当R1为β-D-NAL时，R6为4-NH2-D-Phe，D-Lys，D-Orn，D-Har，D-His，4-gua-D-Phe，D-PAL 或D-Arg。

公开(公告)号：US4605642A

公开(公告)日：1986-08-12

申请号：US583092

申请日：1984-02-23

申请人： Catherine L. Rivier ,  Jean E. F. Rivier ,  Wylie W. Vale, Jr. ,  Marvin R. Brown

发明人： Catherine L. Rivier ,  Jean E. F. Rivier ,  Wylie W. Vale, Jr. ,  Marvin R. Brown

IPC分类号： C07K1/06 ,  A61K38/00 ,  A61K38/04 ,  A61K38/22 ,  A61P5/00 ,  C07K1/02 ,  C07K1/04 ,  C07K14/00 ,  C07K14/575 ,  C07K7/10 ,  A61K37/24

CPC分类号： C07K14/57509 ,  A61K38/00

摘要： Several polypeptide analogs of the known members of the corticotropin releasing factor (CRF) family have been synthesized and tested including human and rat CRF which have the formula: H-Ser-Glu-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Phe-His-Leu-Leu-Arg-Glu-Val-Leu-Glu-Met-Ala-Arg-Ala-Glu-Gln-Leu-Ala-Gln-Gln-Ala-His-Ser-Asn-Arg-Lys-Leu-Met-Glu-Ile-Ile-NH.sub.2. Peptides are herein disclosed that are potent competitive antagonists of CRF in mammals. One which has been found to be particularly potent is: H-Leu-Asp-Leu-Thr-Phe-His-Leu-Leu-Arg-Glu-Met-Leu-Glu-Met-Ala-Lys-Ala-Glu-Gln-Glu-Ala-Glu-Gln-Ala-Ala-Leu-Asn-Arg-Leu-Leu-Leu-Glu-Glu-Ala-NH.sub.2. These antagonists or pharmaceutically or veterinarily acceptable salts thereof, dispersed in a pharmaceutically or veterinarily acceptable liquid or solid carrier, can be administered to mammals, including humans, to achieve a prevent elevation of ACTH, .beta.-endorphin, .beta.-lipotropin, other products of the pro-opiomelanocortin gene and corticosterone levels and/or a lowering of brain-mediated responses to stress over an extended period of time. They may also be used to affect mood, memory and learning, as well as diagnostically.

摘要翻译： 已经合成并测试了促肾上腺皮质激素释放因子（CRF）家族的已知成员的几种多肽类似物，包括人和大鼠CRF，其具有下式：H-Ser-Glu-Glu-Pro-Pro-Ile-Ser-Leu-Asp -Leu-Thr-Phe-His-Leu-Leu-Arg-Glu-Val-Leu-Glu-Met-Ala-Arg-Ala-Glu-Gln-Leu-Ala-Gln-Gln-Ala-His-Ser-Asn -Ar g-Lys-Leu-Met-Glu-Ile-Ile-NH 2。 本文公开了肽，其是哺乳动物中CRF的有竞争力的拮抗剂。 已发现特别有效的是：H-Leu-Asp-Leu-Thr-Phe-His-Leu-Leu-Arg-Glu-Met-Leu-Glu-Met-Ala-Lys-Ala-Glu-Gln -Glu-Ala-Glu-Gln-Ala-Ala-Leu-Asn-Arg-Leu-Leu-Leu-Glu-Glu-Ala-NH 2.这些拮抗剂或其药学或兽医学上可接受的盐， 可以将可接受的液体或固体载体施用于包括人在内的哺乳动物，以达到防止ACTH，β-内啡肽，β-促性腺激素，其他产物的前乳糖皮质激素基因和皮质酮水平的提高和/或降低脑 - 在长时间内介导对压力的反应。 它们也可能用于影响情绪，记忆和学习以及诊断。

公开(公告)号：US4565804A

公开(公告)日：1986-01-21

申请号：US648637

申请日：1984-09-07

申请人： Jean E. F. Rivier ,  Wylie W. Vale, Jr.

发明人： Jean E. F. Rivier ,  Wylie W. Vale, Jr.

IPC分类号： A61K38/04 ,  A61K38/00 ,  A61K38/22 ,  A61P5/00 ,  C07K7/23 ,  C07K14/575 ,  A61K37/02

CPC分类号： C07K7/23 ,  A61K38/00 ,  Y10S930/13

摘要： Peptides which inhibit the secretion of gonadotropins by the pituitary gland and inhibit the release of steroids by the gonads. Administration of an effective amount prevents ovulation of female mammalian eggs and/or the release of steroids by the gonads. The peptides have the structure: X-R.sub.1 -(W)D-Phe-R.sub.3 -R.sub.4 -R.sub.5 -R.sub.6 (V)-R.sub.7 -Arg-Pro-R.sub.10 wherein X is hydrogen or an acyl group having 7 or less carbon atoms; R.sub.1 is dehydro-Pro, Pro, D-pGlu, D-Phe, D-Trp or .beta.-D-NAL; W is F, Cl, Cl.sub.2 Br, NO.sub.2 or C.sup..alpha. Me-Cl; R.sub.3 is D-Trp, (N.sup.in For)D-Trp or D-Trp which is substituted in the 5- or 6-position with NO.sub.2, NH.sub.2, OCH.sub.3, F, Cl, Br or CH.sub.3 ; R.sub.4 is Ser, Orn, AAL or aBu; R.sub.5 is Tyr, (3F)Phe, (2F)Phe, (3I)Tyr, (3CH.sub.3)Phe, (2CH.sub.3)Phe, (3Cl)Phe or (2Cl)Phe; R.sub.6 is D-Lys, D-Orn or D-Dap; V is (arg-R',R").sub.n (X), with n being 1 to 5 and R' and R" being H, methyl, ethyl, propyl or butyl; R.sub.7 is Leu, NML, Nle or Nva; and R.sub.10 is Gly-NH.sub.2, D-Ala-NH.sub.2 or NH-Y, with Y being lower alkyl, cycloalkyl, fluoro lower alkyl or ##STR1## where Q is H or lower alkyl.

摘要翻译： 抑制垂体分泌促性腺激素并抑制性腺释放类固醇的肽。 施用有效量防止雌性哺乳动物卵的排卵和/或性腺释放类固醇。 肽具有以下结构：X-R1-（W）D-Phe-R3-R4-R5-R6（V）-R7-Arg-Pro-R10其中X是氢或具有7个或更少碳原子的酰基; R1是脱氢-Pro，Pro，D-pGlu，D-Phe，D-Trp或β-D-NAL; W是F，Cl，Cl 2 Br，NO 2或CαMe-Cl; R3是在5或6位被NO 2，NH 2，OCH 3，F，Cl，Br或CH 3取代的D-Trp，（NinFor）D-Trp或D-Trp; R4是Ser，Orn，AAL或aBu; R5是Tyr，（3F）Phe，（2F）Phe，（3I）Tyr，（3CH3）Phe，（2CH3）Phe，（3Cl）Phe或（2Cl）Phe; R6是D-Lys，D-Orn或D-Dap; V是（arg-R'，R“'）n（X），n为1至5，R'和R”为H，甲基，乙基，丙基或丁基; R7是Leu，NML，Nle或Nva; 并且R 10是Gly-NH 2，D-Ala-NH 2或NH-Y，其中Y是低级烷基，环烷基，氟低级烷基或者其中Q是H或低级烷基。

公开(公告)号：US5449766A

公开(公告)日：1995-09-12

申请号：US208531

申请日：1994-03-09

申请人： Joan Vaughan ,  Wolfgang H. Fischer ,  Jean E. F. Rivier ,  Jean-Louis M. Nahon ,  Francoise G. Presse ,  Wylie W. Vale, Jr.

发明人： Joan Vaughan ,  Wolfgang H. Fischer ,  Jean E. F. Rivier ,  Jean-Louis M. Nahon ,  Francoise G. Presse ,  Wylie W. Vale, Jr.

IPC分类号： C12N15/09 ,  A61K38/00 ,  A61K38/04 ,  A61P35/00 ,  C07K7/06 ,  C07K7/08 ,  C07K7/64 ,  C07K14/00 ,  C07K14/575 ,  C12N15/12 ,  C12N15/16 ,  C07H12/00 ,  C07H21/00 ,  C07K1/00 ,  C12P21/06

CPC分类号： C07K7/08 ,  C07K7/64 ,  A61K38/00 ,  Y10S530/827 ,  Y10S530/854

摘要： Mammalian melanin-concentrating hormone (MCH) is isolated from rat tissue, purified and characterized. These MCH peptides are useful for treating skin disorders, for suppressing the proliferation of skin tumor cells, such as melanomas in mammals, and for modulating the secretion of ACTH. Generally, peptides are provided which have the following formula: ##STR1## or which are naturally occurring homologs of the peptide with said formula. The peptides which are the naturally occurring MCH homologs of mammalian species other than rat can also be obtained using the materials disclosed, as demonstrated specifically with human MCH, which is found to have the same structure as rat MCH. Also disclosed are the amino acid sequences of, and the nucleotide sequences of the cDNAs which encode, the putative precursors of rat MCH and human MCH. These precursors may also include one or more biologically active peptides N-terminally of the mature MCH's. Among these peptides, which are thought to be formed from the MCH precursors, are the peptide with the sequence H-Glu-Ile-Gly-Asp-Glu-Glu-Asn-Ser-Ala-Lys-Phe-Pro-Ile-NH.sub.2, which is cross-reactive with antibodies against alpha-MSH and CRF, and the peptide with the sequence H-Gly-X.sub.NGE -Phe-Pro-Ala-Glu-Asn-Gly-Val-Gln-Asn-Thr-Glu-Ser-Thr-Gln-Glu-OH, wherein X.sub.NGE is Pro-Ala-Val or Ser-Val-Ala, which is cross-reactive with antibodies against GRF.

摘要翻译： 从大鼠组织中分离哺乳动物黑色素浓缩激素（MCH），进行纯化和表征。 这些MCH肽可用于治疗皮肤病症，抑制皮肤肿瘤细胞增殖，如哺乳动物的黑素瘤，以及调节ACTH的分泌。 通常，提供具有下式的肽：＆lt; IMAGE＆gt;或具有所述式的肽的天然存在同系物。 作为除大鼠之外的哺乳动物物种的天然存在的MCH同源物的肽也可以使用公开的材料获得，如用人MCH特异性证实的，其被发现具有与大鼠MCH相同的结构。 还公开了编码大鼠MCH和人MCH的推定前体的cDNA的氨基酸序列和cDNA的核苷酸序列。 这些前体还可以包括成熟MCH的N-末端的一种或多种生物活性肽。 在这些被认为由MCH前体形成的肽中，具有序列H-Glu-Ile-Gly-Asp-Glu-Glu-Asn-Ser-Ala-Lys-Phe-Pro-Ile-NH 2的肽 ，其与抗α-MSH和CRF的抗体具有交叉反应性，并且具有序列H-Gly-XNGE-Phe-Pro-Ala-Glu-Asn-Gly-Val-Gln-Asn-Thr-Glu-Ser -Thr-Gln-Glu-OH，其中XNGE是Pro-Ala-Val或Ser-Val-Ala，其与抗GRF的抗体交叉反应。

公开(公告)号：US5169932A

公开(公告)日：1992-12-08

申请号：US545239

申请日：1990-06-27

申请人： Carl A. Hoeger ,  Jean E. F. Rivier ,  Paula G. Theobald ,  John S. Porter ,  Catherine L. Rivier ,  Wylie W. Vale, Jr.

发明人： Carl A. Hoeger ,  Jean E. F. Rivier ,  Paula G. Theobald ,  John S. Porter ,  Catherine L. Rivier ,  Wylie W. Vale, Jr.

IPC分类号： A61K38/22 ,  A61K38/00 ,  A61K38/04 ,  C07C279/24 ,  C07C279/28 ,  C07C313/30 ,  C07D249/14 ,  C07K7/02 ,  C07K7/23 ,  C07K14/575

CPC分类号： C07K7/23 ,  C07C279/24 ,  C07C279/28 ,  C07C313/30 ,  C07D249/14 ,  C07K7/02 ,  A61K38/00 ,  C07C2101/14 ,  Y10S514/80 ,  Y10S930/11

摘要： Peptides which include unnatural amino acides and which either inhibit or promote the secretion of gonadotropins by the pituitary gland and inhibit the release of steroids by the gonads. Administration of an effective amount of such peptides that are GnRH antagonists prevents ovulation of female mammalian eggs and/or the release of steroids by the gonads. The antagonists may be used to treat steroid-dependent tumors, such as prostatic and mammary tumors. The peptides are analogs of the decapeptide GnRH wherein there is at least one residue of an unnatural amino acid in the 3-position, the 5-position, the 6-position and/or the 8-position. Such unnatural amino acids are useful in the synthesis of peptides and have the formula U*: ##STR1## where n is an integer from 1 to 6; Y is N--CN, N--CONHR.sub.9, S, O or CH--NO.sub.2 ; R.sub.9 is H, Ac, lower alkyl, aromatic or heterocyclic; X is NH, O, S, M.sub.1 (CH.sub.q).sub.p M.sub.2 or M.sub.1 --(CH.sub.2).sub.p' --M.sub.2 (CH.sub.2).sub.p" --M.sub.3, where M.sub.1 is NR.sub.10, O, S or CHR.sub.3 wherein R.sub.3 is methyl, ethyl, propyl, phenyl, pyridinyl, pyrimidinyl or purinyl, q is 1 or 2; p, p' and p" are integers between O and 6; R.sub.10 is H, lower alkyl or the like, and M.sub.2 and M.sub.3 are M.sub.1, COOH, CONH.sub.2, COOR.sub.3 or CN; R.sub.1 is H, alkyl, modified alkyl, alkenyl, alkynyl, aryl or a direct bond to X; R.sub.2 is R.sub.1, OH, NH.sub.2, NHR.sub.1, or heterocycle.

摘要翻译： 包括非天然氨基酸的肽，其抑制或促进垂体分泌促性腺激素并抑制性腺释放类固醇。 施用有效量的这种肽作为GnRH拮抗剂可防止雌性哺乳动物卵的排卵和/或性腺释放类固醇。 拮抗剂可用于治疗类固醇依赖性肿瘤，例如前列腺和乳腺肿瘤。 肽是十肽GnRH的类似物，其中在3-位，5-位，6-位和/或8-位存在至少一个非天然氨基酸残基。 这种非天然氨基酸可用于肽的合成并具有式U *：其中n是1至6的整数; Y是N-CN，N-CONHR9，S，O或CH-NO2; R9是H，Ac，低级烷基，芳族或杂环基; X是NH，O，S，M1（CHq）pM2或M1-（CH2）p'-M2（CH2）p'-M3，其中M1是NR10，O，S或CHR3，其中R3是甲基，乙基，丙基 ，苯基，吡啶基，嘧啶基或嘌呤基，q为1或2; p，p'和p“是O和6之间的整数; R10为H，低级烷基等，M2和M3为M1，COOH，CONH2，COOR3或CN; R 1是H，烷基，改性烷基，链烯基，炔基，芳基或与X的直接键; R2是R1，OH，NH2，NHR1或杂环。

公开(公告)号：US5109111A

公开(公告)日：1992-04-28

申请号：US498814

申请日：1990-03-23

申请人： Jean E. F. Rivier ,  Wylie W. Vale, Jr. ,  Catherine L. Rivier ,  Jean-Francois Hernandez

发明人： Jean E. F. Rivier ,  Wylie W. Vale, Jr. ,  Catherine L. Rivier ,  Jean-Francois Hernandez

IPC分类号： A61K38/00 ,  C07K14/575

CPC分类号： C07K14/57509 ,  A61K38/00 ,  Y10S514/805 ,  Y10S530/857

摘要： Several known members of the corticotropin releasing factor (CRF) family have been synthesized and tested, including human and rat CRF which have the formula: H-Ser-Glu-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Phe-His- Leu-Leu-Arg-Glu-Val-Leu-Glu-Met-Ala-Arg-Ala-Glu-Gln- Leu-Ala-Gln-Gln-Ala-His-Ser-Asn-Arg-Lys-Leu-Met-Glu- Ile-Ile-NH.sub.2. Peptides are herein disclosed that are potent competitive antagonists of CRF in mammals. One which has been found to be particularly potent is: H-D-Phe-His-Leu-Leu-Arg-Glu-Val-Leu-Glu-Nle-Ala- Arg-Ala-Glu-Gln-Leu-Ala-Gln-Gln-Ala-His-Ser-Asn- Arg-Lys-Leu-Nle-Glu-Ile-Ile-NH.sub.2. One that has shown particularly prolonged duration of potency is: H-D-Phe-His-Leu-Leu-Arg-Glu-Val-Leu-Glu-Nle-Ala- Arg-Ala-Glu-Gln-Leu-Ala-Gln-Gln-Ala-His-Ser-Asn- Arg-Lys-CML-Nle-Glu-Ile-Ile-NH.sub.2. These antagonists or pharmaceutically or veterinarily acceptable salts thereof, dispersed in a pharmaceutically or veterinarily acceptable liquid or solid carrier, can be administered to mammals, including humans, to achieve a prevent elevation of ACTH, .beta.-endorphin, .beta.-lipotropin, other products of the pro-opiomelanocortin gene and corticosterone levels and/or a lowering of brain mediated responses to stress over an extended period of time. They may also be used to affect mood, memory and learning, as well as diagnostically.

摘要翻译： 已经合成并测试了促肾上腺皮质激素释放因子（CRF）家族的几个已知成员，包括人和大鼠CRF，其具有下式：H-Ser-Glu-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu- Thr-Phe-His-Leu-Leu-Arg-Glu-Val-Leu-Glu-Met-Ala-Arg-Ala-Glu-Gln-Leu-Ala-Gln-Gln-Ala-His-Ser-Asn-Arg- Lys-Leu-Met-Glu-Ile-Ile-NH2。 本文公开了肽，其是哺乳动物中CRF的有竞争力的拮抗剂。 已经发现特别有效的是：HD-Phe-His-Leu-Leu-Arg-Glu-Val-Leu-Glu-Nle-Ala-Arg-Ala-Glu-Gln-Leu-Ala-Gln-Gln -Ala-His-Ser-Asn-Arg-Lys-Leu-Nle-Glu-Ile-Ile-NH2。 显示出特别延长的效力持续时间是：HD-Phe-His-Leu-Leu-Arg-Glu-Val-Leu-Glu-Nle-Ala-Arg-Ala-Glu-Gln-Leu-Ala-Gln-Gln -Ala-His-Ser-Asn-Arg-Lys-CML-Nle-Glu-Ile-Ile-NH2。 分散在药学或兽医学上可接受的液体或固体载体中的这些拮抗剂或其药学或兽医学上可接受的盐可以施用于包括人在内的哺乳动物，以达到预防ACTH，β-内啡肽，β-促渗素，其他产物 pro-opiomelanocortin基因和皮质酮水平和/或在长时间内脑介导的应激反应的降低。 它们也可能用于影响情绪，记忆和学习以及诊断。