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    CRF antagonists
    1.
    发明授权
    CRF antagonists 失效
    CRF拮抗剂

    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）。

    CRF antagonists
    2.
    发明授权
    CRF antagonists 失效
    CRF拮抗剂

    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。

    CRF analogs
    3.
    发明授权
    CRF analogs 失效
    CRF类似物

    公开(公告)号：US5439885A

    公开(公告)日：1995-08-08

    申请号：US104862

    申请日：1993-08-10

    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 ,  C07K14/695 ,  A61K38/35

    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 (see SEQ ID NO:9): Y-Ser-Xaa.sub.2 -Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Xaa.sub.12 -His-Leu-Leu-Arg-Glu-Val-Leu-Xaa.sub.20 -Xaa.sub.21 -Xaa.sub.22 -Xaa.sub.23 -Xaa.sub.24 -Xaa.sub.25 -Gln-Leu-Ala-Gln-Gln-Ala-Xaa.sub.32 -Ser-Asn-Arg-Xaa.sub.36 -Leu-Xaa.sub.38 -Xaa.sub.39 -Ile-Xaa.sub.41 -NH.sub.2, wherein Y is an acyl group having 7 or fewer carbon atoms or hydrogen; Xaa.sub.2 is Glu or Gln; Xaa.sub.12 is Phe or D-Phe; Xaa.sub.20 is Ala or Glu; Xaa.sub.21 is Met or Nle; Xaa.sub.22 is Ala or Thr; Xaa.sub.23 is Arg or Lys; Xaa.sub.24 is D-Ala or Ala; Xaa.sub.25 is Glu or Asp; Xaa.sub.32 is D-His or His; Xaa.sub.36 is Lys or Arg; Xaa.sub.38 is Met, Nle or Leu; Xaa.sub.39 is Ala, Glu or Asp; Xaa.sub.41 is Ile or Ala; provided however that at least one of Xaa.sub.20 and Xaa.sub.39 is Ala and that the N-terminus may be shortened by a sequence of up to about 5 residues. By shortening the N-terminus by 11 residues, particularly potent CRF antagonists are created. These analogs or their pharmaceutically acceptable salts, dispersed in an acceptable liquid or solid carrier, can be administered to humans.

    摘要翻译： 公开了基于hCRF，oCRF和α螺旋CRF的CRF的类似物，其可以被施用以实现ACTH，β-内啡肽，β-促肌动蛋白，其前产妇的皮质酮皮质酮水平的其他产物和皮​​质酮水平的显着升高 。 类似物包括具有式（见SEQ ID NO：9）的那些：Y-Ser-Xaa2-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Xaa12-His-Leu-Leu-Arg-Glu -Val-Leu-Xaa20-Xaa21-Xaa22-Xaa23-Xaa24-Xaa25-Gln-Leu-Ala-Gln-Gln-Ala-Xaa32-Ser-Asn-Arg-Xaa36-Leu-Xaa38-Xaa39-Ile-Xaa41-NH2 其中Y是具有7个或更少碳原子或氢的酰基; Xaa2是Glu或Gln; Xaa12是Phe或D-Phe; Xaa20是Ala或Glu; Xaa21是Met或Nle; Xaa22是Ala或Thr; Xaa23是Arg或Lys; Xaa24是D-Ala或Ala; Xaa25是Glu或Asp; Xaa32是D-His或他的; Xaa36是Lys或Arg; Xaa38是Met，Nle或Leu; Xaa39是Ala，Glu或Asp; Xaa41是Ile或Ala; 但是，Xaa20和Xaa39中的至少一个是Ala，并且N末端可以被至多约5个残基的序列缩短。 通过将N末端缩短11个残基，产生特别有效的CRF拮抗剂。 分散在可接受的液体或固体载体中的这些类似物或其药学上可接受的盐可以施用于人。

    CRF analogs
    4.
    发明授权
    CRF analogs 失效
    CRF模拟

    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.