公开(公告)号：US5510458A

公开(公告)日：1996-04-23

申请号：US162178

申请日：1993-12-14

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

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

IPC分类号： A61K38/00 ,  C07K14/575 ,  C07K14/695

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-Xaa.sub.13 -Leu-Leu-Arg-Xaa.sub.17 -Xaa.sub.18 -Leu-Xaa.sub.20 -Nle-Xaa.sub.22 -Xaa.sub.23 -Xaa.sub.24 -Xaa.sub.25 -Xaa.sub.26 -Leu-Xaa.sub.28 -Xaa.sub.29 -Gln-Xaa.sub.31 -Xaa.sub.32 -Xaa.sub.33 -Xaa.sub.34 -Arg-Xaa.sub.36 -Xaa.sub.37 -Nle-Xaa.sub.39 -Xaa.sub.40 -Xaa.sub.41 -NH.sub.2 wherein Y is Ac or hydrogen; Xaa.sub.13 is His, Tyr or Glu; Xaa.sub.17 is CML, Glu, Asn or Lys; Xaa.sub.18 is Val, Nle or Met; Xaa.sub.20 is Glu, D-Glu, Aib or D-Ala; Xaa.sub.22 is Ala, Aib, Thr, Asp or Glu; Xaa.sub.23 is Arg, Orn, Har or Lys; Xaa.sub.24 is Ala or Aib; Xaa.sub.25 is Asp or Glu; Xaa.sub.26 is Gln, Asn or Lys; Xaa.sub.28 is Ala or Aib; Xaa.sub.29 is Gln, Aib or Glu, Xaa.sub.31 is Ala or Aib; Xaa.sub.32 is His, Aib, Gly, Tyr or Ala; Xaa.sub.33 is Ser, Aib, Asn, Leu, Thr or Ala; Xaa.sub.34 is Asn or Aib; Xaa.sub.36 is Lys, Orn, Arg, Har or Leu; Xaa.sub.37 is Leu or Tyr; Xaa.sub.39 is Glu, Aib or Asp; Xaa.sub.40 is Ile, Aib, Thr, Glu, Ala, Val, Leu, Nle, Phe, Nva, Gly or Gln; and Xaa.sub.41 is Ala, Ile, Gly, Val, Leu, Nle, Phe, Nva or Gln, wherein CML may be substituted for Leu. 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.34 !-rCRF (12-41) , D-Phe.sup.12, CML.sup.17, Nle.sup.21,38 !-rCRF(12-41) , D-Phe.sup.12, Aib.sup.20, Nle.sup.21,38 !-rCRF(12-41), D-Phe.sup.12, Aib.sup.29, Nle.sup.21,38 !-rCRF(12-41), D-Phe.sup.12, CML.sup.14, Nle.sup.21,38, Aib.sup.24,28,31 !-rCRF(12-41) and D-Phe.sup.12, CML.sup.15, Aib.sup.24,28,31 !-rCRF(12-41).

摘要翻译： PCT No.PCT / US92 / 05101 Sec。 371日期：1993年12月14日 102（e）日期1993年12月14日PCT提交1992年6月12日PCT公布。 出版物WO92 / 22576 日期为1992年12月23日。公开的是改进的CRF肽拮抗剂，例如具有下式的那些：YD-Phe-Xaa13-Leu-Leu-Arg-Xaa17-Xaa18-Leu-Xaa20-Nle-Xaa22-Xaa23-Xaa24-Xaa25- Xaa26-Leu-Xaa28-Xaa29-Gln-Xaa31-Xaa32-Xaa33-Xaa34-Arg-Xaa36-Xaa37-Nle-Xaa39-Xaa40-Xaa41-NH2，其中Y是Ac或氢; Xaa13是His，Tyr或Glu; Xaa17是CML，Glu，Asn或Lys; Xaa18是Val，Nle或Met; Xaa20是Glu，D-Glu，Aib或D-Ala; Xaa22是Ala，Aib，Thr，Asp或Glu; Xaa23是Arg，Orn，Har或Lys; Xaa24是Ala或Aib; Xaa25是Asp或Glu; Xaa26是Gln，Asn或Lys; Xaa28是Ala或Aib; Xaa29是Gln，Aib或Glu，Xaa31是Ala或Aib; Xaa32是His，Aib，Gly，Tyr或Ala; Xaa33是Ser，Aib，Asn，Leu，Thr或Ala; Xaa34是Asn或Aib; Xaa36是Lys，Orn，Arg，Har或Leu; Xaa37是Leu或Tyr; Xaa39是Glu，Aib或Asp; Xaa40是Ile，Aib，Thr，Glu，Ala，Val，Leu，Nle，Phe，Nva，Gly或Gln; Xaa41是Ala，Ile，Gly，Val，Leu，Nle，Phe，Nva或Gln，其中CML可以被Leu取代。 公开的具体CRF拮抗剂包括[D-Phe12，D-Ala20，Nle21,38] -rCRF（12-41），[D-Phe12，Nle21,38，Aib34] -rCRF（12-41），[D-Phe12， C-17，Nle 21,38] -rCRF（12-41），[D-Phe12，Aib20，Nle21,38] -rCRF（12-41），[D-Phe12，Aib29，Nle21,38] -rCRF（12-41 ），[D-Phe12，CML14，Nle21,38，Aib24,28,31] -rCRF（12-41）和[D-Phe12，CML15，Aib24,28,31] -rCRF（12-41）。

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：US4661472A

公开(公告)日：1987-04-28

申请号：US732531

申请日：1985-05-09

申请人： Jean E. F. Rivier ,  Janos I. Varga ,  Arnold T. Hagler ,  R. Scott Struthers ,  Marilyn H. Perrin ,  Catherine L. Rivier ,  Wylie W. Vale, Jr.

发明人： Jean E. F. Rivier ,  Janos I. Varga ,  Arnold T. Hagler ,  R. Scott Struthers ,  Marilyn H. Perrin ,  Catherine L. Rivier ,  Wylie W. Vale, Jr.

IPC分类号： A61K38/04 ,  A61K38/00 ,  A61K38/22 ,  A61K38/27 ,  A61P5/00 ,  C07K7/06 ,  C07K7/23 ,  C07K14/00 ,  C07K14/575 ,  A61K37/43

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 of such GnRH antagonists prevents ovulation of female mammalian eggs and/or the release of steroids by the gonads. These peptides may be used to treat steroid-dependent tumors, such as prostatic and mammary tumors. The peptides are cyclic analogs of the decapeptide GnRH wherein there is a covalent bond between the residue in the 4-position and the residue in the 10-position. Examples of such bonds include the disulfide linkage between Cys residues, an amide linkage between a side chain amino group and a side chain carboxyl group, a dicarba linkage between side-chain alkyl groups, and a carba linkage between a side-chain alkyl group and a side-chain sulfhydryl group.

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。 施用有效量的这种GnRH拮抗剂防止雌性哺乳动物卵的排卵和/或性腺释放类固醇。 这些肽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的环状类似物，其中在4-位的残基与10位的残基之间存在共价键。 这些键的实例包括Cys残基之间的二硫键，侧链氨基和侧链羧基之间的酰胺键，侧链烷基之间的二链键和侧链烷基与侧链烷基之间的碳键 侧链巯基。

公开(公告)号：US4307083A

公开(公告)日：1981-12-22

申请号：US147555

申请日：1980-05-08

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

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

IPC分类号： A61K38/00 ,  C07K7/16 ,  C07K7/23 ,  A61K37/00 ,  C07C103/52

CPC分类号： C07K7/23 ,  C07K7/16 ,  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:R.sub.1 -R.sub.2 -R.sub.3 -Ser-Tyr-R.sub.4 -R.sub.5 -Arg-R.sub.6wherein R.sub.1 is selected from the group consisting of dehydro Pro, dehydro D-Pro, Acetyl dehydro Pro and acetyl dehydro D-Pro; R.sub.2 is selected from the group consisting of D-Phe, Phe, N.alpha.Me-Phe, His, D-His, D-Trp, Trp and N.alpha.Me-Leu; R.sub.3 is selected from the group consisting of D-Trp, Trp D-Phe, Phe, Pro and D-His; R.sub.4 is selected from the group consisting of Gly, D-Trp, D-Phe, imBzl-D-His and D-Tyr; R.sub.5 is selected from the group consisting of Leu and N.alpha.Me-Leu; and R.sub.6 is selected from the group consisting of Pro-Gly-NH.sub.2 and Pro-NH-CH.sub.2 -CH.sub.3.

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：R1-R2-R3-Ser-Tyr-R4-R5-Arg-R6，其中R1选自脱氢Pro，脱氢D-Pro，乙酰脱氢Pro和乙酰基脱氢D-Pro; R2选自D-Phe，Phe，NαMe-Phe，His，D-His，D-Trp，Trp和NαMe-Leu; R3选自D-Trp，Trp D-Phe，Phe，Pro和D-His; R4选自Gly，D-Trp，D-Phe，imBzl-D-His和D-Tyr; R5选自Leu和NαMe-Leu; 并且R 6选自Pro-Gly-NH 2和Pro-NH-CH 2 -CH 3。

公开(公告)号：US5043322A

公开(公告)日：1991-08-27

申请号：US223277

申请日：1988-07-22

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

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

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

CPC分类号： C07K14/60 ,  A61K38/00

摘要： Synthetic peptides which stimulate the release of pituitary GH in animals, including humans, and are more resistant to enzymatic degradation in the body than hGRF having the sequence: (B)R.sub.1 -R.sub.2 R.sub.3 -Ala-Ile-Phe-Thr-R.sub.8 -Ser-R.sub.10 -Arg-R.sub.12 R.sub.13 -Leu-R.sub.15 -Gln-Leu-R.sub.18 -Ala-Arg-R.sub.21 -R.sub.22 -Leu-R.sub.24 -R.sub.25 -Ile-R.sub.27 -R.sub.28 -R.sub.29 -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, D-Met, Phe, D-Phe, pCl-Phe, Leu, His or D-His; B is H, C.sup.a Me, N.sup.1 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.8 is Ser, Asn, Lys, Arg, Asp or Gln; 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, Ala or .beta.-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 cys, abu, asp, glu, orn, lys, dab or dap; R.sub.27 is Met, D-Met, Ala, Nle, Ile, Leu, Nva or Val; R.sub.28 is Asn or Ser; R.sub.29 is cys, abu, asp, glu, orn, lys, dab or dap; 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 or Ala; R.sub.43 is Asn or Arg; R.sub.44 is a natural amino acid, such as Leu or Val. C-terminal sequences of from 1 to 15 residues beginning at R.sub.44 and extending as far as up to R.sub.29 may be deleted. These peptides as well as their nontoxic salts may also be used diagnostically.

公开(公告)号：US4415558A

公开(公告)日：1983-11-15

申请号：US378999

申请日：1982-05-17

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

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

IPC分类号： A61K38/00 ,  C07K14/575 ,  A61K37/00 ,  C07C103/52

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

摘要： CRF (Corticotropin Releasing Factor) has the formula:H-Ser-Gln-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Phe-His-Leu-Leu-Arg-Glu-Val-Leu-Glu-Met-Thr-Lys-Ala-Asp-Gln-Leu-Ala-Gln-Gln-Ala-His-Ser-Asn-Arg-Lys-Leu-Leu-Asp-Ile-Ala-NH.sub.2.Analogs have been synthesized that are at least as potent as CRF, and CRF or these analogs or pharmaceutically acceptable salts thereof, dispersed in a pharmaceutically acceptable liquid or solid carrier, can be administered to mammals to achieve a substantial elevation of ACTH, .beta.-endorphin, .beta.-lipotropin and corticosterone levels and/or a lowering of blood pressure over an extended period of time. In the analogs, one or more of the first three N-terminal residues may be deleted or may be substituted by a peptide up to 10 amino acids long and/or by an acylating agent containing up to 7 carbon atoms. Ala in the 41-position may also be substituted or deleted so long as the remaining C-terminus is amidated. Several other substitutions may also be made throughout the chain.

摘要翻译： CRF（促皮质素释放因子）具有下式：H-Ser-Gln-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Phe-His-Leu-Leu-Arg-Glu-Val-Leu- Glu-Met-Thr-Lys-Ala-Asp-Gln-Leu-Ala-Gln-Gln-Ala-His-Ser-Asn-Ar g-Lys-Leu-Leu-Asp-Ile-Ala-NH 2。 已经合成至少与CRF一样有效的类似物，并且分散在药学上可接受的液体或固体载体中的CRF或这些类似物或其药学上可接受的盐可以施用于哺乳动物以实现ACTH，β-内啡肽的显着升高 ，β-促凝血酶和皮质酮水平和/或在长时间内降低血压。 在类似物中，前三个N末端残基中的一个或多个可以被缺失或可被长达10个氨基酸的肽和/或被含有至多7个碳原子的酰化剂所取代。 41位的Ala也可以被取代或缺失，只要其余的C末端被酰胺化即可。 还可以在整个链中进行几个其它取代。

公开(公告)号：US4215038A

公开(公告)日：1980-07-29

申请号：US950301

申请日：1978-10-16

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

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

IPC分类号： A61K38/00 ,  C07K7/16 ,  C07K7/23 ,  C07C103/52 ,  A61K37/00

CPC分类号： C07K7/23 ,  C07K7/16 ,  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. The peptides have the structure:R.sub.1 --R.sub.2 --R.sub.3 --Ser--Tyr--R.sub.4 --R.sub.5 --Arg--R.sub.6wherein R.sub.1 is selected from the group consisting of D-pGlu, D-Pro, D-Trp, D-His, D-Arg, D-Leu, Formyl D-Pro, Acetyl D-Pro, Benzoyl D-Pro and .beta.-Ala; R.sub.2 is selected from the group consisting of D-Phe, Phe, N.alpha. Me-Phe, His, D-His, D-Trp, Trp and N.alpha. Me-Leu; R.sub.3 is selected from the group consisting of D-Trp, Trp; D-Phe, Phe, Pro and D-His; R.sub.4 is selected from the group consisting of Gly, D-Trp, D-Phe and D-Tyr; R.sub.5 is selected from the group consisting of Leu and N.alpha. Me Leu; and R.sub.6 is selected from the group consisting of Pro-Gly-NH.sub.2 and Pro--NH--CH.sub.2 --CH.sub.3.

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。 肽具有以下结构：R1-R2-R3-Ser-Tyr-R4-R5-Arg-R6，其中R1选自D-pGlu，D-Pro，D-Trp，D-His， Arg，D-Leu，甲酰基D-Pro，乙酰基D-Pro，苯甲酰基D-Pro和β-Ala; R2选自D-Phe，Phe，NαMe-Phe，His，D-His，D-Trp，Trp和NαMe-Leu; R3选自D-Trp，Trp; D-Phe，Phe，Pro和D-His; R4选自Gly，D-Trp，D-Phe和D-Tyr; R5选自Leu和NαMe Leu; 并且R 6选自Pro-Gly-NH 2和Pro-NH-CH 2 -CH 3。

公开(公告)号：US4489061A

公开(公告)日：1984-12-18

申请号：US423734

申请日：1982-09-27

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

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

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

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

摘要： Peptides which are LRF analogs that inhibit the secretion of gonadotropins by the pituitary gland and inhibit the release of steroids by the gonads can be effective to suppress androgen-dependent behavior when administered to male mammals. The peptides are LRF antagonists having a binding affinity at least about 15 times that exhibited by LRF and having an ICR.sub.50 of less than 1/1. Examples of peptides which may be used are those having the structure:R.sub.1 -R.sub.2 -R.sub.3 -D-Trp-Ser-Tyr-R.sub.4 -Leu-Arg-Pro-Gly-NH.sub.2 wherein R.sub.1 is selected from the group consisting of hydrogen, formyl, acetyl, acrylyl, benzoyl and allyl; R.sub.2 is selected from the group consisting of dehydro Pro, dehydro D-Pro, Thz and D-Thz; R.sub.3 is selected from the group consisting of pCl-D-Phe, pF-D-Phe, pNO.sub.2 -D-Phe and 3,4 Cl-D-Phe; R.sub.4 is selected from the group consisting of D-Trp and (imBzl) D-His; and Leu may be substituted by N.alpha.MeLeu.Effective suppression of androgen-dependent behavior is achieved at a daily dosage level of not more than about 3 mg. per Kg. of body weight.

摘要翻译： 作为抑制垂体分泌促性腺激素并抑制性腺释放类固醇的LRF类似物的肽在施用于雄性哺乳动物时可有效抑制雄激素依赖性行为。 肽是LRF拮抗剂，其结合亲和力至少约为LRF显示的约15倍，ICR50小于1/1。 可以使用的肽的实例是具有以下结构的那些：R1-R2-R3-D-Trp-Ser-Tyr-R4-Leu-Arg-Pro-Gly-NH2，其中R1选自氢，甲酰基 ，乙酰基，丙烯酰基，苯甲酰基和烯丙基; R2选自脱氢Pro，脱氢D-Pro，Thz和D-Thz; R3选自pCl-D-Phe，pF-D-Phe，pNO 2 -D-Phe和3,4 C-D-Phe; R4选自D-Trp和（imBz1）D-His; Leu可被NαMeLeu取代。 在不超过约3mg的日剂量水平下实现雄激素依赖性行为的有效抑制。 每公斤 的体重。

公开(公告)号：US4377574A

公开(公告)日：1983-03-22

申请号：US272968

申请日：1981-06-12

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

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

IPC分类号： A61K38/00 ,  C07K7/23 ,  A61K37/00 ,  C07C103/52

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

摘要： Peptides which are LRF analogs that inhibit the secretion of gonadotropins by the pituitary gland and inhibit the release of steroids by the gonads can be effective contraceptives when administered to male mammals. The peptides are LRF antagonists having a binding affinity at least about 15 times that exhibited by LRF and having an ICR.sub.50 of less than 1/l. Examples of peptides which may be used are those having the structure:R.sub.1 --R.sub.2 --R.sub.3 --D--Trp--Ser--Tyr--R.sub.4 --Leu--Arg--Pro--Gly--NH.sub.2wherein R.sub.1 is selected from the group consisting of hydrogen, formyl, acetyl, acrylyl, benzoyl and allyl; R.sub.2 is selected from the group consisting of dehydro Pro, dehydro D--Pro, Thz and D--Thz; R.sub.3 is selected from the group consisting of pCl--D--Phe, pF--D--Phe, pNO.sub.2 --D--Phe and 3,4 Cl--D--Phe; R.sub.4 is selected from the group consisting of D--Trp and (imBzl) D--His; and Leu may be substituted by N MeLeu.Effective contraception is achieved at a daily dosage level of not more than about 3 mg. per Kg. of body weight.

摘要翻译： 作为LRP类似物的肽，其通过垂体抑制促性腺激素的分泌并且抑制性腺释放类固醇在施用于雄性哺乳动物时可以是有效的避孕药。 肽是LRF拮抗剂，其结合亲和力至少约为LRF显示的约15倍，ICR50小于1 / l。 可以使用的肽的实例是具有以下结构的那些：R1-R2-R3-D-Trp-Ser-Tyr-R4-Leu-Arg-Pro-Gly-NH2，其中R1选自氢，甲酰基 ，乙酰基，丙烯酰基，苯甲酰基和烯丙基; R2选自脱氢Pro，脱氢D-Pro，Thz和D-Thz; R3选自pCl-D-Phe，pF-D-Phe，pNO 2 -D-Phe和3,4 C-D-Phe; R4选自D-Trp和（imBz1）D-His; Leu可被N MeLeu取代。 在不超过约3mg的日剂量水平下实现有效的避孕。 每公斤 的体重。

公开(公告)号：US5493006A

公开(公告)日：1996-02-20

申请号：US078558

申请日：1993-06-16

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

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

IPC分类号： A61K38/00 ,  C07K14/575 ,  C07K14/695

CPC分类号： C07K14/57509 ,  A61K38/00

摘要： Improved CRF peptide antagonists have the formula: ##STR1## wherein R.sub.20 is Cys or Glu; R.sub.23 is Cys, Lys or Orn; provided that when R.sub.20 is Cys, R.sub.23 is Cys and when R.sub.20 is Glu, R.sub.23 is Lys or Orn; or a nontoxic addition salt thereof. Specific CRF antagonists disclosed include (cyclo 20-23) [D-Phe.sup.12, Lys.sup.23, Nle.sup.21,38, ]rCRF(12-41); (cyclo 20-23) [D-Phe.sup.12, Orn.sup.23, Nle.sup.21,38 ]rCRF(12-41) and (cyclo 20-23) [D-Phe.sup.12, Cys.sup.20, Cys.sup.23, Nle.sup.21,38 ]rCRF(12-41).

摘要翻译： 改进的CRF肽拮抗剂具有下式：其中R 20是Cys或Glu; R23是Cys，Lys或Orn; 条件是当R 20为Cys时，R 23为Cys，当R 20为Glu时，R 23为Lys或Orn; 或其无毒的加成盐。 公开的具体CRF拮抗剂包括（环20-23）[D-Phe12，Lys23，Nle21,38] rCRF（12-41）; （环20-23）[D-Phe12，Orn23，Nle21,38] rCRF（12-41）和（环20-23）[D-Phe12，Cys20，Cys23，Nle21,38] rCRF（12-41）。