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31. 发明授权

US5777073A Cyclic CRF antagonist peptides 失效
标题翻译：循环CRF拮抗肽
公开(公告)号：US5777073A
公开(公告)日：1998-07-07
申请号：US865773
申请日：1997-05-30
申请人： Jean E. F. Rivier
发明人： Jean E. F. Rivier
IPC分类号： A61K38/00 , A61P1/00 , A61P25/00 , C07K14/575 , G01N33/15 , G01N33/50 , G01N33/566 , G01N33/74 , A61K38/28 , A61K38/35 , C07K5/00 , C07K7/00
CPC分类号： G01N33/566 , C07K14/57509 , G01N33/74 , A61K38/00 , G01N2333/5751 , Y10S930/26 , Y10S930/27
摘要： Novel cyclic CRF antagonist peptides are created by shortening the N-terminus of a CRF family peptide by 8-11 residues and adding an acyl group. CML is preferably present in what would be the 27-position of the native CRF sequence, and D-Tyr may be incorporated at the N-terminus to facilitate labelling. The cyclizing bond is preferably created between the side chains of the residues in positions 30 and 33; but it may alternatively be created between the residues in either of positions 28 and 29 with those in positions 31 and 32 or with those in positions 32 and 33, respectively. The side chain of Lys in position 33 is preferably linked to the side chain of Glu in position 30 by a lactam bridge to form the cyclic peptide. Disclosed CRF antagonists include: (cyclo 30-33) �Ac-Asp.sup.9, D-Phe.sup.12, Nle.sup.21,38, CML.sup.27,40, Glu.sup.30, Lys.sup.33 !r/hCRF(9-41), (cyclo 30-33) �Ac-Asp.sup.9, D-Phe.sup.12, Nle.sup.21,38, CML.sup.27,37, Glu.sup.30, Lys.sup.33 !r/hCRF(9-41), (cyclo 30-33) �Ac-Asp.sup.9, D-Phe.sup.12, CML.sup.14,27, Nle.sup.21,38, Glu.sup.30, Lys.sup.33 !r/hCRF(9-41), (cyclo 30-33) �Ac-Asp.sup.9, D-Phe.sup.12, Nle.sup.21,38, CML.sup.27, Glu.sup.30, Lys.sup.33 !r/hCRF(9-41), (cyclo 30-33) �Ac-Asp.sup.9, D-Phe.sup.12, CML.sup.18,27, Nle.sup.21,38, Glu.sup.30, D-His.sup.32, Lys.sup.33 !r/hCRF(9-41) and (cyclo 30-33) �Ac-Asp.sup.9, D-Phe.sup.12, CML.sup.18,27, Nle.sup.21,38, Glu.sup.30, Lys.sup.33 !r/hCRF(9-41).
摘要翻译：通过将CRF家族肽的N末端缩短8-11个残基并加入酰基来产生新的循环CRF拮抗剂肽。 CML优选存在于天然CRF序列的27位上，并且D-Tyr可以并入N末端以促进标记。优选在位置30和33之间的残基的侧链之间产生环化键; 但也可以分别在位置28和29之间的残基与位置31和32中的残基之间或位于第32和33位的残基之间产生。位置33处的Lys侧链优选通过内酰胺桥连接于位置30的Glu侧链以形成环肽。公开的CRF拮抗剂包括：（环30-33）[Ac-Asp9，D-Phe12，Nle21,38，CML27,40，Glu30，Lys33] r / hCRF（9-41），（环30-33）[Ac- Asp9，D-Phe12，Nle21,38，CML27,37，Glu30，Lys33] r / hCRF（9-41），（环30-33）[Ac-Asp9，D-Phe12，CML14,27，Nle21,38， Glu30，Lys33] r / hCRF（9-41），（环30-33）[Ac-Asp9，D-Phe12，Nle21,38，CML27，Glu30，Lys33] r / hCRF（9-41），（环30 -33）[Ac-Asp9，D-Phe12，CML18,27，Nle21,38，Glu30，D-His32，Lys33] r / hCRF（9-41）和（环30-33）[Ac-Asp9， Phe12，CML18,27，Nle21,38，Glu30，Lys33] r / hCRF（9-41）。

32. 发明授权

US5493006A Cyclic CRF analogs 失效
标题翻译：循环CRF类似物
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）。

33. 发明授权

US5371070A Bicyclic GnRH antagonists and a method for regulating the secretion of gonadotropins 失效
标题翻译：双环GnRH拮抗剂和调节促性腺激素分泌的方法
公开(公告)号：US5371070A
公开(公告)日：1994-12-06
申请号：US973989
申请日：1992-11-09
申请人： Steven C. Koerber , John S. Porter , Jean E. F. Rivier
发明人： Steven C. Koerber , John S. Porter , Jean E. F. Rivier
IPC分类号： A61K38/00 , C07K7/02 , C07K7/23 , C07K7/06 , A61K37/38 , C07K5/12
CPC分类号： C07K7/02 , C07K7/23 , A61K38/00
摘要： Peptides which have substantial bioactivity to inhibit the secretion of gonadotropins by the pituitary gland and to inhibit the release of steroids by the gonads. Administration of an effective amount of such GnRH antagonists prevents ovulation and/or the release of steroids by the gonads. They may also be used to treat steroid-dependent tumors, such as prostatic and mammary tumors. The peptides are bicyclic analogs of the decapeptide GnRH having two covalent bonds, between the residues in the 4- and 10-positions and the residues in the 5- and 8-positions. The latter linkage includes peptide bonds between a residue of an .alpha.-amino acid outside of the main chain and a side-chain carboxyl group of the 5-position residue and a side-chain amino group of the 8-position residue.
摘要翻译：具有大量生物活性以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拮抗剂可防止性腺的排卵和/或释放类固醇。它们也可用于治疗类固醇依赖性肿瘤，如前列腺和乳腺肿瘤。肽是具有两个共价键的十肽GnRH的双环类似物，在4-和10-位之间的残基和5-和8-位的残基之间。后一连接包括在主链外部的α-氨基酸的残基与5位残基的侧链羧基和8位残基的侧链氨基之间的肽键。

34. 发明授权

US5296468A GnRH analogs 失效
标题翻译： GnRH类似物
公开(公告)号：US5296468A
公开(公告)日：1994-03-22
申请号：US6729
申请日：1993-01-21
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： A61K38/00 , C07C279/24 , C07C279/28 , C07C313/30 , C07D249/14 , C07K7/02 , C07K7/23 , A61K37/38 , C07K7/06 , C07K7/20
CPC分类号： C07K7/02 , C07C279/24 , C07C279/28 , C07C313/30 , C07D249/14 , C07K7/23 , A61K38/00 , C07C2101/14 , Y10S514/80 , Y10S930/11
摘要： Peptides which include unnatural amino acids 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-, 5-, 6- and/or 8-positions. Such unnatural amino acids are useful in the synthesis of peptides and have the formula U.sup.* : ##STR1## where W is (CH.sub.2).sub.n or ##STR2## n is an integer from 1 to 6; and j=1, 2 or 3. Preferably, either Y is N--CN, X is NH and R.sub.2 is alkyl, modified alkyl, alkenyl, alkynyl, aryl or methyl pridyl or ##STR3## where R.sub.11 is H or acyl.
摘要翻译：包括非天然氨基酸的肽，其通过垂体抑制或促进促性腺激素的分泌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/或由性腺释放类固醇。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-，5-，6-和/或8-位存在至少一个非天然氨基酸残基。这样的非天然氨基酸可用于肽的合成，并具有其中W是（CH 2）n或（*化学结构*）n是1至6的整数的式U *：（*化学结构*）; 优选地，Y是N-CN，X是NH，R 2是烷基，改性烷基，链烯基，炔基，芳基或甲基酰基或（*化学结构*），其中R 11是H或酰基。

35. 发明授权

US5262519A GRF analogs XI 失效
标题翻译： GRF类似物XI
公开(公告)号：US5262519A
公开(公告)日：1993-11-16
申请号：US701414
申请日：1991-05-15
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 , C07K7/00 , C07K14/575 , C07K14/60 , A61K37/02 , A61K37/00 , C07K5/00
CPC分类号： C07K14/60
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. Certain preferred peptides have the formula:(B)R.sub.1 -Ala-Asp-Ala-Ile-Phe-Thr-R.sub.8 -Ser-Tyr-Arg-Lys-Val-Leu-R.sub.15 -R.sub.16 - Leu-Ser-Ala-Arg-Lys-Leu-Leu-R.sub.24 -R.sub.25 -Ile-Nle-R.sub.28 -Arg-Y wherein R.sub.1 is Tyr, D-Tyr, Phe, D-Phe, His or D-His; B is H or N.sup..alpha. Me; R.sub.8 is Ala, Aib or Asn; R.sub.15 is Gly or Ala; R.sub.16 is Ala, Aib or Gln; R.sub.24 is Ala, Aib or Gln; R.sub.25 is Ala, Aib or Asp; R.sub.28 is Ser or Asn; Y is NHR with R being H or lower alkyl; provided that at least one of R.sub.8, R.sub.16, R.sub.24 and R.sub.25 is Ala or Aib.

36. 发明授权

US5245009A CRF antagonists 失效
标题翻译： 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）。

37. 发明授权

US5235036A CRF analogs 失效
标题翻译： 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.

38. 发明授权

US5169935A Method of making peptides 失效
标题翻译：制作肽的方法
公开(公告)号：US5169935A
公开(公告)日：1992-12-08
申请号：US541810
申请日：1990-06-20
申请人： Carl A. Hoeger , Paula G. Theobald , John S. Porter , Jean E. F. Rivier
发明人： Carl A. Hoeger , Paula G. Theobald , John S. Porter , Jean E. F. Rivier
IPC分类号： C07K1/06 , C07K7/23
CPC分类号： C07K1/064 , C07K7/23 , Y02P20/55
摘要： Methods for making peptides of a suitable length for solid phase synthesis, which peptides include in their sequence a pair of residues of a different character which have acylated side chains and a residue which has an N-alkylated side chain. A peptide intermediate is constructed on the resin using commercially available starting materials. The N-terminus can be acylated by removing the .alpha.-amino protecting group and acylating under standard conditions. First primary amino protecting groups included in those residues to be acylated are removed, and acylation is effected, preferably by using a carboxypyridine or a similar heterocyclic acylating agent. Following such side chain acylation, a second protecting group included in the residue to be N-alkylated is removed, and the N-alkylation reaction is carried out while the peptide remains on the resin using a borohydride and an appropriate aldehyde or ketone. Following cleavage from the resin and removal of any protecting groups still remaining, the peptide is appropriately purified, thus requiring only a single purification to be carried out while forming a synthetic peptide including residues for which the modified amino acids are not readily commercially available.
摘要翻译：制备用于固相合成的合适长度的肽的方法，该肽在其序列中包括具有酰化侧链的不同特征的残基和具有N-烷基化侧链的残基。使用市售原料在树脂上构建肽中间体。可以通过除去α-氨基保护基并在标准条件下酰化来酰化N-末端。除去要被酰化残留物中包括的第一个伯氨基保护基，优选通过使用羧基吡啶或类似的杂环酰化剂进行酰化。在这样的侧链酰化之后，除去待N-烷基化的残基中的第二保护基，并且使用硼氢化钠和适当的醛或酮在肽保留在树脂上的同时进行N-烷基化反应。在从树脂切割并除去仍然保留的任何保护基之后，肽被适当地纯化，因此仅需要进行单次纯化，同时形成包含修饰氨基酸不容易商业获得的残基的合成肽。

39. 发明授权

US5098995A GRF Analogs VIIA 失效
标题翻译： GRF类似物VIIA
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。

40. 发明授权

US4740500A GnRH antagonists VIII 失效
标题翻译： GnRH拮抗剂VIII
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。

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