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公开(公告)号：US4518586A
公开(公告)日：1985-05-21
申请号：US545094
申请日：1983-10-25
IPC分类号： C12P21/00 , A23K1/16 , A61K38/00 , A61K38/04 , A61K38/18 , A61K38/22 , A61K38/25 , C07K14/00 , C07K14/575 , C07K14/60 , C07K14/61 , C12P21/02 , C07C103/52 , A61K37/02
CPC分类号： C07K14/60 , A23K20/147 , A61K38/00 , Y10S930/12
摘要： Human parcreatic GRF(hpGRF), rat hypothalamic GRF(rGRF) and porcine hypothalamic GRF(pGRF) have been earlier characterized and synthesized. The invention provides synthetic peptides which are extremely potent in stimulating the release of pituitary GH in animals, including humans, which have resistance to enzymatic degradation in the body, and which have the sequence: 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-R.sub.17 -R.sub.18 -Ala-Arg-Lys-Leu-R.sub.23 -R.sub.24 -R.sub.25 -Ile-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 having either a C.sup..alpha. Me or N.sup..alpha. Me substitution or being unsubstituted; R.sub.2 is Ala or D-Ala; R.sub.3 is Asp or D-Asp; R.sub.8 is Ser, Asn, D-Ser or D-Asn; R.sub.10 is Tyr or D-Tyr; R.sub.12 is Arg or Lys; R.sub.13 is Ile or Val; R.sub.15 is Gly or D-Ala; R.sub.17 is Leu or D-Leu; R.sub.18 is Tyr or Ser; R.sub.23 is Leu or D-Leu; R.sub. 24 is His or Gln; R.sub.25 is Glu, Asp, D-Glu or D-Asp; 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 Arg or Ser; R.sub.38 is Gln or Arg; R.sub.39 is Arg or Gly; R.sub.40 is Ser or Ala; R.sub.42 is Phe, Ala or Val; R.sub.43 is Asn or Arg; R.sub.44 is a natural amino acid; provided however that either R.sub.17 or R.sub.23 is D-Leu or R.sub.25 is either D-Glu or D-Asp and that any or all of the residues between R.sub.29 and R.sub.44, inclusive, may be deleted; or a nontoxic salt thereof. The carboxyl moiety of the amino acid residue at the C-terminus can be the radical --COOR,--CRO,--CONHNHR,--CON(R)(R') or --CH.sub.2 OR, with R and R' being lower alkyl, fluoro lower alkyl or hydrogen. These peptides as well as nontoxic salts thereof may be administered to animals, including humans and cold-blooded animals, to stimulate the release of GH and may be used diagnostically.
摘要翻译： 人胰腺GRF（hpGRF），大鼠下丘脑GRF（rGRF）和猪下丘脑GRF（pGRF）已被早期表征和合成。 本发明提供了合成肽，其在刺激体内对酶降解的抗性的动物（包括人）中的垂体GH的释放方面非常有效，并且具有以下顺序：R1-R2-R3-Ala-Ile-Phe- Thr-R8-Ser-R10-Arg-R12-R13-Leu-R15-Gln-R17-R18-Al-Arg-Lys-Leu-R23-R24-R25-Ile-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 或具有CαMe或NαMe取代或未被取代的D-His; R2是Ala或D-Ala; R3是Asp或D-Asp; R8是Ser，Asn，D-Ser或D-Asn; R10是Tyr或D-Tyr; R12是Arg或Lys; R13是Ile或Val; R15是Gly或D-Ala; R17是Leu或D-Leu; R18是Tyr或Ser; R23为Leu或D-Leu; R 24是His或Gln; R25是Glu，Asp，D-Glu或D-Asp; R27是Met，D-Met，Ala，Nle，Ile，Leu，Nva或Val; R28为Asn或Ser; R34是Arg或Ser; R38是Gln或Arg; R39是Arg或Gly; R40是Ser或Ala; R42是Phe，Ala或Val; R43是Asn或Arg; R44是天然氨基酸; 但是R17或R23是D-Leu或R25是D-Glu或D-Asp，并且R29和R44之间的任何或全部残基可以被缺失; 或其无毒盐。 C末端的氨基酸残基的羧基部分可以是基团-COOR，-CRO，-CONHNHR，-CON（R）（R'）或-CHOOR，其中R和R'是低级烷基，氟低级 烷基或氢。 这些肽及其无毒盐可以施用于动物，包括人和冷血动物，以刺激GH的释放并且可以在诊断上使用。
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公开(公告)号：US4393050A
公开(公告)日：1983-07-12
申请号：US258878
申请日：1981-04-29
IPC分类号： C07K14/575 , A61K38/00 , A61K38/04 , A61P5/00 , A61P5/02 , C07K14/655 , A61K37/00 , C07C103/52
CPC分类号： C07K14/6555 , A61K38/00 , Y10S514/806 , Y10S514/866 , Y10S514/926 , Y10S514/927 , Y10S930/16
摘要： Somatostatin-28 has the formula: ##STR1## Analogs have been synthesized that are more potent than somatostatin-28, and these analogs or pharmaceutically acceptable salts thereof, dispersed in a pharmaceutically acceptable liquid or solid carrier, can be administered to mammals in the same manner as somatostatin. In the analogs, Leu may be substituted in the 8-position in combination with D-Trp in the 22-position and/or Tyr in the 25-position. D-Cys may also be substituted in the 28-position, and D-Ser may be substituted in the 27-position. Certain residues may also be deleted. D-Trp.sup.22 somatostation-28 has surprisingly been found to be insulin-selective when administered in vivo and is useful for the treatment of insulinoma.
摘要翻译： 生长抑素-28具有以下分子式：H-Ser-Ala-Asn-Ser-Asn-Pro-Ala-Met-Ala-Pro-Arg-Glu-Arg-Lys- 分散在药学上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以与生长抑素相同的方式施用于哺乳动物。 在类似物中，Leu可以在D位的8位上与22位和/或25位的Tyr结合取代。 D-Cys也可以在28位被取代，D-Ser可以在27位被取代。 某些残基也可能被删除。 D-Trp22生长激素-28在体内给药时已被惊人地发现是胰岛素选择性的，并且可用于治疗胰岛素瘤。
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公开(公告)号：US4382922A
公开(公告)日：1983-05-10
申请号：US353237
申请日：1982-03-01
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： LRF analogs having a modified D-Phe residue in the 6-position act as superagonists exhibiting potencies many times more than that of LRF. The peptides or their nontoxic salts can be administered by intravenous, subcutaneous, sublingual, oral, intravaginal, intranasal or rectal routes. The peptides can be used to regulate fertility in male and female mammals, including human beings.The peptides are represented by the following formula:p-Glu-His-Trp-Ser-Ty-R.sub.1 -Leu-Arg-Pro-NH-CH.sub.2 -CH.sub.3wherein R.sub.1 is selected from the group consisting of methyl-D-Phe, nitro-D-Phe, and methyoxy-D-Phe.
摘要翻译： 在6位具有修饰的D-Phe残基的LRF类似物作为表现出比LRF多很多倍的潜能的超级拮抗剂。 肽或其无毒盐可以通过静脉内，皮下，舌下，口服，阴道内，鼻内或直肠途径施用。 这些肽可用于调节男性和女性哺乳动物（包括人类）的生育力。 肽由下式表示：p-Glu-His-Trp-Ser-Ty-R1-Leu-Arg-Pro-NH-CH2-CH3，其中R1选自甲基-D-Phe，硝基 -D-Phe和甲氧基-D-Phe。
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公开(公告)号：USRE30548E
公开(公告)日：1981-03-17
申请号：US071559
申请日：1979-08-31
IPC分类号： A61K38/00 , C07K14/655
CPC分类号： C07K14/6555 , A61K38/00
摘要： The present invention relates to peptides which possess biological activity in respect to the inhibition of growth hormone, insulin .[.secretion.]. and glucagon secretion .[.are provided.].. The peptides have fewer amino acid components than somatostatin and some of the peptides have dissociated activity. .Iadd.
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公开(公告)号：US5439885A
公开(公告)日：1995-08-08
申请号：US104862
申请日：1993-08-10
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。
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公开(公告)号：US5015729A
公开(公告)日：1991-05-14
申请号：US210683
申请日：1988-06-23
IPC分类号： A61K38/00 , C07K14/575 , C07K16/26
CPC分类号： C07K14/575 , C07K16/26 , A61K38/00
摘要： A dimeric protein with inhibin activity is isolated from ram reta testis fluid using reverse-phase high-performance liquid chromatography and gel filtration. The isolated molecule is composed of two chains having apparent molecular weights of about 18,000 and about 16,500 to 14,500 Daltons, as measured by gel electrophoresis, which are bound together by disulfide bonding and the longer of which is likely glycosylated. Microsequencing revealed the NH.sub.2 -terminal portion of the longer chain to be Ser- Thr-Pro-Pro-Leu-Pro-Trp-Pro-Trp-Ser-Pro-Ala-Ala-Leu-Arg-Leu-Gln-Arg-Pro-Pro- Glu-Glu-Pro-Ala-Ala-His-Ala-Asp-Cys and of the shorther chain to by Gly-Leu-Glu-Cys-Asp-Gly-Lys-Val-Asn-Ile-Cys-Cys-Lys-Lys-Gln-Phe. This dimeric protein specifically inhibits basal secretion of FSH, but not of LH, in a rat anterior pituitary monolayer culture system, exhibiting a half-maximal effective dose of about 0.1 to 0.3 ng/ml. Furthermore, antibodies raised against synthetic replicates of the N-terminal six residues of the longer chain, as well as against the N-terminal 25 residues, are effective to reduce the activity of highly purified intact ovine inhibin and might be used to exert a profertility effect in rams, ewes and other mammals.
摘要翻译： 使用反相高效液相色谱和凝胶过滤从ram reta睾丸液中分离具有抑制素活性的二聚体蛋白。 分离的分子由具有约18,000和约16,500至14,500道尔顿的两条链组成，通过凝胶电泳测量，其通过二硫键结合在一起，并且其中较长的可能被糖基化。 Microsequencing显示较长链的NH 2末端部分为Ser-Thr-Pro-Pro-Leu-Pro-Trp-Pro-Trp-Ser-Pro-Ala-Ala-Leu-Arg-Leu-Gln-Arg-Pr 通过Gly-Leu-Glu-Cys-Asp-Gly-Lys-Val-Asn-Ile-Cys-Ala-Pro-Glu-Glu-Pro-Ala-Ala-His-Ala-Asp-Cys， Cys-Lys-Lys-Gln-Phe。 这种二聚体蛋白特异性抑制大鼠垂体前叶垂体单层培养系统中FSH的基础分泌而不是LH分泌，表现出约0.1至0.3ng / ml的最大有效剂量。 此外，针对长链的N末端六个残基以及N末端25个残基的合成重复产生的抗体对于降低高度纯化的完整羊抑制素的活性是有效的，并且可以用于发挥促进作用 对公羊，母羊和其他哺乳动物的影响。
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公开(公告)号：US4973577A
公开(公告)日：1990-11-27
申请号：US091696
申请日：1987-08-31
申请人： Wylie W. Vale, Jr. , Jean E. F. Rivier , Richard A. McClintock , Anne Corrigan , Joan Vaughan , Joachim Spiess , Nicholas C. Ling , Shao-Yao Ying , Frederick S. Esch , Roger C. L. Guillemin
发明人： Wylie W. Vale, Jr. , Jean E. F. Rivier , Richard A. McClintock , Anne Corrigan , Joan Vaughan , Joachim Spiess , Nicholas C. Ling , Shao-Yao Ying , Frederick S. Esch , Roger C. L. Guillemin
IPC分类号： A61K38/00 , C07K14/575
CPC分类号： C07K14/575 , A61K38/00 , Y10S514/80
摘要： A 28,000-dalton protein with FSH-releasing activity is isolated from porcine follicular fluid in a multi-step procedure including gel filtration, ion exchange chromatography and several reverse-phase high-performance liquid chromatography steps. The 28 kD protein promotes secretion of FSH, but not of LH, in a rat anterior pituitary monolayer culture system, exhibiting an EC.sub.50 of 0.5 ng/ml. These peptides are dimers of inhibin .beta.-chains of mammals, and homodimers or heterodimers of the .beta..sub.A and .beta..sub.B chains are biologically active to regulate fertility of various mammalian species, including humans.
摘要翻译： 具有FSH释放活性的28,000道尔顿蛋白质以多步法从猪滤泡液中分离，包括凝胶过滤，离子交换层析和几个反相高效液相色谱步骤。 在大鼠垂体前叶单层培养系统中，28kD蛋白促进FSH的分泌，但不促进LH的分泌，其表现为0.5ng / ml的EC 50。 这些肽是哺乳动物的抑制素β-链的二聚体，βA和βB链的同源二聚体或异源二聚体具有生物学活性，以调节各种哺乳动物物种（包括人类）的生育力。
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公开(公告)号：US4843064A
公开(公告)日：1989-06-27
申请号：US96513
申请日：1987-09-11
CPC分类号： C07K14/60 , A61K38/00 , Y10S930/12
摘要： The invention provides peptides which are particularly potent in stimulating the release of pituitary GH in fish and amphibians and which have a substantial portion or all of the following sequence: His-Ala-Asp-Gly-R.sub.5 -Phe-Asn-Lys-Ala-Tyr-Arg-Lys-Ala-Leu-Gly-Gln-Leu- Ser-Ala-Arg-Lys-Tyr-Leu-His-Thr-Leu-R.sub.27 -R.sub.28 -R.sub.29 -R.sub.30 -R.sub.31 -Gly-R.sub.33 -R.sub.34 -R.sub.35 -R.sub.36 -R.sub.37 - R.sub.38 -R.sub.39 -R.sub.40 -R.sub.41 -R.sub.42 -R.sub.43 -R.sub.44 -Ser wherein R.sub.5 is Met, Leu, Val, Nva, Gln, Thr, Ile or Nle; R.sub.27 is Met, Leu, Val, Nva, Gln, Thr, Ile or Nle; R.sub.28 is Ala, Ser or Asn; R.sub.29 is Lys or Arg; R.sub.30 is Arg or Gln; R.sub.31 is Val or Gln; R.sub.33 is Gly or Glu; R.sub.34 is Gly, Arg or Ser; R.sub.35 is Ser or Asn; R.sub.36 is Met, Leu, Val, Nva, Gln, Thr, Ile or Nle; R.sub.37 is Ile or Glu; R.sub.38 is Glu, Gln or Arg; R.sub.39 is Asp, Arg or Gly; R.sub.40 is Asp, Ser or Ala; R.sub.41 is Asn, Arg or Lys; R.sub.42 is Glu, Phe, Ala or Val; R.sub.43 is Pro, Asn or Arg; R.sub.44 is Leu or Ala. A sequence beginning at the C-terminus and extending part way or all the way to residue R.sub.27 may be deleted; a 29-residue peptide beginning at the N-terminus may be preferred. These peptides, as well as their nontoxic salts, are considered to be particularly useful in agriculture.
摘要翻译： 本发明提供了在刺激鱼类和两栖动物中垂体GH释放特别有效的肽，其具有大部分或全部以下序列：His-Ala-Asp-Gly-R5-Phe-Asn-Lys-Ala- Tyr-Arg-Lys-Ala-Leu-Gly-Gln-Leu- Ser-Ala-Arg-Lys-Tyr-Leu-His-Thr-Leu-R27-R28-R29-R30-R31-Gly-R33-R34- R3为R5，R36-R37-R38-R39-R40-R41-R42-R43-R44-Ser，其中R5为Met，Leu，Val，Nva，Gln，Thr，Ile或Nle; R27是Met，Leu，Val，Nva，Gln，Thr，Ile或Nle; R28是Ala，Ser或Asn; R29为Lys或Arg; R30是Arg或Gln; R31为Val或Gln; R33是Gly或Glu; R34是Gly，Arg或Ser; R35是Ser或Asn; R36是Met，Leu，Val，Nva，Gln，Thr，Ile或Nle; R37是Ile或Glu; R38是Glu，Gln或Arg; R39为Asp，Arg或Gly; R40是Asp，Ser或Ala; R41是Asn，Arg或Lys; R42是Glu，Phe，Ala或Val; R43是Pro，Asn或Arg; R44是Leu或Ala，从C-末端开始并延伸到残基R27的一部分或全部的序列可以被删除; 可以优选从N末端开始的29残基肽。 这些肽以及它们的无毒盐被认为在农业中特别有用。
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公开(公告)号：US4703035A
公开(公告)日：1987-10-27
申请号：US782912
申请日：1985-10-02
CPC分类号： C07K14/60 , A61K38/00 , Y10S930/12
摘要： Surprisingly active fragments of human pancreatic GRF have been synthesized which exhibit good biological activity. These synthetic peptides are extremely potent in stimulating the release of pituitary GH in humans and in nonhuman animals and have the general formula: H-Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-Gly-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Met-Ser-Arg-Y wherein Y is NH.sub.2, Gln-NH.sub.2, Gln-Gln-NH.sub.2 or Gln-Gln-Gly-NH.sub.2. Two such fragments have been tested, namely the 29 and the 32 N-terminal residue sequences that are amidated at the C-terminus. These peptides, as well as nontoxic salts thereof, may be administered therapeutically to animals, including humans.
摘要翻译： 已经合成了人胰腺GRF的惊人活性片段，其表现出良好的生物学活性。 这些合成肽在刺激人和非人动物中垂体GH的释放方面非常有效，具有以下通式：H-Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys -Val-Leu-Gly-Gln-Leu- Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Met-Ser-Arg-Y，其中Y是NH2，Gln-NH2，Gln-Gln-NH2 或Gln-Gln-Gly-NH 2。 已经测试了两个这样的片段，即在C末端酰胺化的29个和32个N-末端残基序列。 这些肽以及其无毒盐可以治疗性地给予动物，包括人。
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公开(公告)号：US4689396A
公开(公告)日：1987-08-25
申请号：US771517
申请日：1985-08-30
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, which can be used for therapeutic treatment. The peptides have the structure:X-R.sub.1 -R.sub.2 -R.sub.3 -Ser-Arg-R.sub.6 -R.sub.7 -Arg-Pro-R.sub.10 wherein X is hydrogen, Acr or Ac; R.sub.1 is .beta.-D-2NAL, dehydroPro or 4Cl-D-Phe; R.sub.2 is Cl-D-Phe, F-D-Phe, NO.sub.2 -D-Phe, Br-D-Phe or C.sup.a Me/Cl-D-Phe; R.sub.3 is D-Trp or .beta.-D-2NAL; R.sub.6 is D-Tyr, .beta.-D-2NAL or D-Arg; R.sub.7 is Leu or NML; and R.sub.10 is Gly-NH.sub.2, NHCH.sub.2 CH.sub.3 or D-Ala-NH.sub.2 ; provided however that R.sub.1 or R.sub.3 or both are .beta.-D-2NAL.
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