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101. 发明授权

US5278146A CRF analogs 失效
标题翻译： CRF类似物
公开(公告)号：US5278146A
公开(公告)日：1994-01-11
申请号：US905564
申请日：1992-06-29
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 , C07K14/575 , A61K37/40 , C07K7/38
CPC分类号： C07K14/57509 , A61K38/00
摘要： Analogs of CRF, which are based upon hCRF, oCRF, sauvagine 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 and/or an increase in blood pressure over an extended period of time. One CRF agonist which has been found to be particularly potent is: H-Ser-Gln-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-D-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. In these agonist analogs, one or more of the first six N-terminal residues may be deleted and/or the N-terminal alpha-amino group may be acylated by an acylating agent containing up to 7 carbon atoms. A number of other substitutions may also be made throughout the chain. These analogs 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. These analogs may also be used as stimulants to elevate mood and improve memory and learning, as well as diagnostically.
摘要翻译：公开了基于hCRF，oCRF，sauvagine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） - 促性腺激素，其他产物的显着升高 - 皮质酮皮质素基因和皮质酮水平和/或长时间的血压升高。已经发现特别有效的一种CRF激动剂是：H-Ser-Gln-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-D-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-NH2 。在这些激动剂类似物中，前6个N末端残基中的一个或多个可以被缺失，和/或N-末端α-氨基可以被含有至多7个碳原子的酰化剂酰化。还可以在整个链中进行许多其它取代。分散在药学上或兽医学上可接受的液体或固体载体中的这些类似物或其药学或兽医学上可接受的盐可以施用于哺乳动物，包括人。这些类似物也可以用作兴奋剂以提高心情，改善记忆和学习以及诊断。

102. 发明授权

US5132111A CRF analog conjugates 失效
标题翻译： CRF类似物共轭物
公开(公告)号：US5132111A
公开(公告)日：1992-07-21
申请号：US508258
申请日：1990-04-11
申请人： Wylie W. Vale, Jr. , Jean E. F. Rivier , Jeffrey Schwartz
发明人： Wylie W. Vale, Jr. , Jean E. F. Rivier , Jeffrey Schwartz
IPC分类号： C07K14/575
CPC分类号： C07K14/57509 , Y10S514/805 , Y10S530/807 , Y10S930/28
摘要： Agonists and antagonists of rCRF are disclosed that exhibit good binding affinity to CRF receptors. One exemplary agonist is: H-Ser-Gln-Glu-Pro-Pro-Ile-Ser- Leu-Asp-Leu-Thr-Phe-His-Leu-Leu-Arg-Glu-Met-Leu-Glu-Met- Ala-Arg-Ala-Glu-Gln-Glu-Ala-Glu-Gln-Ala-Ala-Leu-Asn-Arg- Leu-Leu-Leu-Glu-Glu-Ala-NH.sub.2. In the agonists, one or more of the first five N-terminal residues may be deleted or may be substituted by a peptide up to 10 amino acids long. A number of other substitutions may also be made throughout the chain. Similar peptides which function as CRF antagonists are created by deleting the first 7, 8 or 9 N-terminal residues. These analogs are coupled to a cytotoxin, such as gelonin, by a dialdehyde or the like, e.g., glutaraldehyde. The conjugates may be used to eliminate CRF Target Cells, and thus to regulate secretion of ACTH, .beta.-lipotropin and the like. Such conjugates can also be administered to alleviate conditions associated with hyperactivity of the hypothalamus-pituitary adrenal axis as well as neoplastic diseases associated with tumors that express CRF receptor.
摘要翻译：公开了rCRF的激动剂和拮抗剂，其表现出对CRF受体的良好结合亲和力。一个示例性的激动剂是：H-Ser-Gln-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Phe-His-Leu-Leu-Arg-Glu-Met-Leu-Glu-Met- -Arg-Ala-Glu-Gln-Glu-Ala-Glu-Gln-Ala-Ala-Leu-Asn-Arg-Leu-Leu-Leu-Glu-Glu-Ala-NH2。在激动剂中，前5个N-末端残基中的一个或多个可以被缺失，或者可被长达10个氨基酸的肽取代。还可以在整个链中进行许多其它取代。作为CRF拮抗剂起作用的相似肽通过缺失第7,8或9个N-末端残基而产生。这些类似物通过二醛或类似物例如戊二醛与细胞毒素（例如gelonin）偶联。缀合物可用于消除CRF靶细胞，并因此调节ACTH，β-Lipotropin等的分泌。也可以施用这样的缀合物以减轻与下丘脑 - 垂体肾上腺轴的多动症相关的病症以及与表达CRF受体的肿瘤相关的肿瘤疾病。

103. 发明授权

US5112809A CRF analogs 失效
标题翻译： CRF类似物
公开(公告)号：US5112809A
公开(公告)日：1992-05-12
申请号：US615838
申请日：1990-11-20
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 , C07K14/575
CPC分类号： C07K14/57509 , A61K38/00
摘要： Analogs of 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 and/or a lowering of blood pressure over an extended period of time. One analog which has been found to be particularly preferred is: [His.sup.20, Nle.sup.21, Leu.sup.38 ]-rCRF. In the analogs, one or more of the first five N-terminals 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. A number of other substitutions may also be made throughout the chain. These analogs or pharmaceutically or veterinarily acceptable salts thereof, dispersed in a pharmaceutically or veterinarily acceptable liquid or solid carrier, can be administered to mammels, including humans. These analogs may also be used as stimulants to elevate mood and improve memory and learning.
摘要翻译：公开了CRF的类似物，其可被施用以实现ACTH，β-内啡肽，β-促纤维素，其他产物的原乳糖皮质素基因和皮质酮水平的显着升高和/或在延长的时间段内降低血压。已经发现特别优选的一种类似物是：[His20，Nle21，Leu38] -rCRF。在类似物中，前5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。还可以在整个链中进行许多其它取代。分散在药学上或兽医学上可接受的液体或固体载体中的这些类似物或其药学或兽医学上可接受的盐可被施用于包括人在内的哺乳动物。这些类似物也可以用作兴奋剂以提高心情，改善记忆和学习。

104. 发明授权

US4908352A Urotensin peptides 失效
标题翻译：促肾上腺素肽
公开(公告)号：US4908352A
公开(公告)日：1990-03-13
申请号：US101580
申请日：1987-09-28
申请人： Karl P. Lederis , Denis McMaster , Jean E. F. Rivier
发明人： Karl P. Lederis , Denis McMaster , Jean E. F. Rivier
IPC分类号： A61K38/00 , C07K14/575
CPC分类号： C07K14/57509 , A61K38/00
摘要： Maggy UI (Urotensin I) or flathead sole urotensin, obtained from Hippoglossides Elassodon has the formula: H-Ser-Glu-Glu-Pro-Pro-Met-Ser-Ile-Asp-Leu-Thr-Phe-His-Met-Leu-Arg-Asn-Met-Ile-His-Arg-Ala-Lys-Met-Glu-Gly-Glu-Arg-Glu-Gln-Ala-Leu-Ile-Asn-Arg-Asn-Leu-Leu-Asp-Glu-Val-NH.sub.2. Analogs have been synthesized that are at least as potent as Maggy UI, and Maggy UI or such an analog or a biologically active fragment of either or pharmaceutically acceptable salts of any of the foregoing, dispersed in a pharmaceutically acceptable liquid or solid carrier, can be administered to mammals to achieve a substantial elevation of ACTH, .beta.-endorphin, .alpha.-lipotropin and corticosterone levels and/or an increase in intestinal blood flow and/or a lowering of systemic blood pressure and/or a changing of regional blood distributio over an extended period of time. In the analogs, one or more of the first three N-terminal residues is deleted and is optionally substituted by a peptide fragment up to 5 amino acids long, and/or an acylating agent containing up to 7 carbon atoms is optionally added at the N-terminus.
摘要翻译：由Hippoglossides Elassodon得到的Maggy UI（Urotensin I）或扁平头状的单独的urotensin具有下式：H-Ser-Glu-Glu-Pro-Pro-Met-Ser-Ile-Asp-Leu-Thr-Phe-His-Met-Leu -Arg-Asn-Met-Ile-His-Arg-Ala-Lys-Met-Glu-Gly-Glu-Arg-Glu-Gln-Ala-Leu-Ile-Asn-Ar g-Asn-Leu-Leu-Asp- Glu-Val-NH2。已经合成类似物至少与Maggy UI一样有效，Maggy UI或分散在药学上可接受的液体或固体载体中的前述任何一种或其药学上可接受的盐的类似物或生物活性片段可以是施用于哺乳动物以实现ACTH，β-内啡肽，α-促肌动蛋白和皮质酮水平的显着升高和/或肠血流量的增加和/或全身血压的降低和/或区域血液分布的变化延长一段时间在类似物中，前三个N-末端残基中的一个或多个被缺失，并且任选地被长达5个氨基酸的肽片段取代，和/或任选地在N个加入含有至多7个碳原子的酰化剂 -terminus。

105. 发明授权

US4728726A GRF analogs IIIb 失效
标题翻译： GRF类似物IIIb
公开(公告)号：US4728726A
公开(公告)日：1988-03-01
申请号：US939342
申请日：1986-12-08
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 , C07K14/60 , C07K7/10
CPC分类号： C07K14/60 , A61K38/00 , Y10S930/12 , Y10S930/32
摘要： Human GRF(hGRF), rat GRF(rGRF), porcine GRF(pGRF), ovine GRF(oGRF) and bovine GRF(bGRF) 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 contain 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 -R.sub.14 -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 -R.sub.29 -R.sub.30 -R.sub.31 -R.sub.32, wherein R.sub.1 is Tyr, D-Tyr, Met, Phe, D-Phe, pCl-Phe, Leu, His or D-His having either a C.sup.a Me or N.sup.a Me substitution or being unsubstituted; R.sub.2 is Ala, D-Ala or D-NMA; 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.14 is Leu or D-Leu, 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, Ser or desR.sub.28 ; R.sub.29 is Arg, D-Arg or desR.sub.29 ; R.sub.30 is Gln or desR.sub.30 ; R.sub.31 is Glu or desR.sub.31 ; and R.sub.32 is Gly or desR.sub.32. These peptides as well as their nontoxic salts may also be used diagnostically.
摘要翻译：人GRF（hGRF），大鼠GRF（rGRF），猪GRF（pGRF），羊GRF（oGRF）和牛GRF（bGRF）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动物（包括人）的垂体GH的释放方面非常有效，并且含有以下序列：R1-R2-R3-Ala-Ile-Phe- Thr-R8-Ser-R10-Arg-R12-R13-R14-R15-Gln-R17-R18-Al-Arg-Lys-Leu-R23-R24-R25-Ile-R27-R28-R29-R30-R31 -R32，其中R1是具有CaMe或NaMe取代或未取代的Tyr，D-Tyr，Met，Phe，D-Phe，pCl-Phe，Leu，His或D-His; R2是Ala，D-Ala或D-NMA; 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; R14为Leu或D-Leu，R15为Gly或D-Ala; R17是Leu或D-Leu; R18是Tyr或Ser; R23为Leu或D-Leu; R24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，Ser或desR28; R29是Arg，D-Arg或desR29; R30是Gln或desR30; R31是Glu或desR31; 而R32是Gly或desR32。这些肽以及它们的无毒盐也可以在诊断上使用。

106. 发明授权

US4628043A Hypothalamic GRF agonists 失效
标题翻译：下丘脑GRF激动剂
公开(公告)号：US4628043A
公开(公告)日：1986-12-09
申请号：US714687
申请日：1985-03-21
申请人： Joachim Spiess , Jean E. F. Rivier , Wylie W. Vale, Jr.
发明人： Joachim Spiess , Jean E. F. Rivier , Wylie W. Vale, Jr.
IPC分类号： A23K1/16 , A61K38/00 , C07K14/60 , A61K37/43 , C07K7/10
CPC分类号： C07K14/60 , A23K20/147 , A61K38/00 , Y10S930/12
摘要： Synthetic peptides are provided which are extremely potent in stimulating the release of pituitary GH in animals and which have the formula: H--R.sub.1 --Ala--Asp--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--Lys--Leu--Leu--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 --Leu--Y wherein R.sub.1 is Tyr, Met, Leu, D--Tyr, D--His or His; R.sub.8 is Ser or 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.18 is Tyr or Ser; R.sub.24 is His or Gln; R.sub.25 is Glu or Asp; R.sub.27 is Met, Ala, Nle, Ile, Leu 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 or Ala; R.sub.43 is Asn or Arg; and Y represents the carboxyl moiety of the amino acid residue at the C-terminus and is 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, or a fragment thereof extending from the N-terminus in a continuous sequence at least to the residue in position 29, which fragment is biologically active to cause the release of GH from the pituitary, or a nontoxic salt of such peptide or peptide fragment. The peptides are analogs of human GRF and contain at least two but less than all of the following residues: R.sub.8 is Asn, R.sub.12 is Lys, R.sub.13 is Val, R.sub.18 is Ser, R.sub.24 is Gln, R.sub.25 is Asp, R.sub.28 is Ser.
摘要翻译：提供了合成肽，其在刺激动物中垂体GH的释放方面非常有效，其具有下式：H-R1-Ala-Asp-Ala-Ile-Phe-Thr-R8-Ser-R10-Arg-R12-R13 -Leu-R15-Gln-Leu-R1 8-Ala-Arg-Lys-Leu-Leu-R24-R25-Ile-R27-R28-Arg-Gln-Gln-Gly-Glu-R34-Asn-Gln-Glu- R38-R39-R40-Arg-R42-R43-Leu-Y，其中R1是Tyr，Met，Leu，D-Tyr，D-His或His; R8是Ser或Asn; R10是Tyr或D-Tyr; R12是Arg或Lys; R13是Ile或Val; R15是Gly或D-Ala; R18是Tyr或Ser; R24是His或Gln; R25是Glu或Asp; R27是Met，Ala，Nle，Ile，Leu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或Ala; R43是Asn或Arg; 并且Y代表C末端的氨基酸残基的羧基部分，并且是基团-COOR，-CRO，-CONHNHR，-CON（R）（R'）或-CH 2 OR，其中R和R'是低级烷基，氟低级烷基或氢，或其从N末端以连续序列至少延伸至位置29的残基的片段，该片段具有生物学活性以引起GH从垂体中释放，或无毒盐这样的肽或肽片段。肽是人GRF的类似物，并且含有至少两个但少于所有以下残基：R8是Asn，R12是Lys，R13是Val，R18是Ser，R24是Gln，R25是Asp，R28是Ser。

107. 发明授权

US4626523A GRF analogs II 失效
标题翻译： GRF类似物II
公开(公告)号：US4626523A
公开(公告)日：1986-12-02
申请号：US742736
申请日：1985-06-10
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： A23K1/16 , A61K38/00 , C07K14/60 , C07K7/10 , A61K37/24
CPC分类号： C07K14/60 , A23K20/147 , A61K38/00 , Y10S930/32
摘要： Human pancreatic GRF(hpGRF) and rat hypothalamic GRF(rhGRF) 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 are resistant to enzymatic degradation in the body, and which have the sequence: R.sub.1 -Ala-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-Lys-Leu-Leu-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 -Y wherein R.sub.1 is Tyr, D-Tyr, Met, Phe, D-Phe, pCl-Phe, Leu, His or D-His having either a C.sup.a Me or N.sup.a Me substitution; 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.18 is Tyr or Ser; R.sub.24 is His or Gln; R.sub.25 is Glu or Asp; R.sub.27 is 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 or Ala; R.sub.43 is Asn or Arg; R.sub.44 is a natural amino acid. Any or all of the residues between R.sub.28 and R.sub.44, inclusive, can be deleted, and 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）和大鼠下丘脑GRF（rhGRF）已被早期表征和合成。本发明提供了合成肽，其在刺激对包括人在内的动物（包括人）在内的动物体内释放垂体GH是非常有效的，其具有以下序列：R1-Ala-R3-Ala-Ile-Phe- Thr-R8-Ser-R10-Arg-R12-R13-Leu-R15-Gln-Leu-R18-Aa-Arg-Lys-Leu-Leu-R24-R25-Ile-R27-R28-Arg-Gln-Gln -Gly-Glu-R34-Asn-Gln-Glu-R38-R39-R40-Arg-R42-R43-R44-Y其中R1是Tyr，D-Tyr，Met，Phe，D-Phe，pCl-Phe，Leu ，His或D-His具有CaMe或NaMe取代基; 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; R18是Tyr或Ser; R24是His或Gln; R25是Glu或Asp; R27是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或Ala; R43是Asn或Arg; R44是天然氨基酸。可以缺失R28和R44之间的任何或全部残基，其中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-CH 2 OR，其中R和R'为低级烷基，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。

108. 发明授权

US4595676A Rat hypothalamic GRF 失效
标题翻译：大鼠下丘脑GRF
公开(公告)号：US4595676A
公开(公告)日：1986-06-17
申请号：US488748
申请日：1983-04-26
申请人： Joachim Spiess , Jean E. F. Rivier , Wylie W. Vale, Jr.
发明人： Joachim Spiess , Jean E. F. Rivier , Wylie W. Vale, Jr.
IPC分类号： C07K14/61 , A23K1/16 , A61K38/00 , A61K38/25 , C07K14/60 , C07K7/10 , A61K37/43
CPC分类号： C07K14/60 , A23K20/147 , A61K38/00 , Y10S930/12
摘要： Rat hypothalamic GRF has been synthesized and has the formula: H-His-Ala-Asp-Ala-Ile-Phe-Thr-Ser-Ser-Tyr-Arg-Arg-Ile-Leu-Gly-Gln-Leu-Tyr-Ala-Arg-Lys-Leu-Leu-His-Glu-Ile-Met-Asn-Arg-Gln-Gln-Gly-Glu-Arg-Asn-Gln-Glu-Gln-Arg-Ser-Arg-Phe-Asn-OH. The peptide is believed to be and is hereinafter referred to as rhGRF (for rat hypothalamic GH releasing factor). The invention provides synthetic peptides which are extremely potent in stimulating the release of pituitary GH in animals and which have the formula: H-R.sub.1 -Ala-Asp-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-Lys-Leu-Leu-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 -Y wherein R.sub.1 is Tyr, Met, D-Tyr, Leu, D-His or His; R.sub.8 is Ser or 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.18 is Tyr or Ser; R.sub.24 is His or Gln; R.sub.25 is Glu or Asp; R.sub.27 is Met, Ala, Nle, Ile, Leu 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 or Ala; R.sub.43 is Asn or Arg; R.sub.44 is a natural amino acid or des-R.sub.44 ; and Y signifies the carboxyl moiety of the amino acid residue at the C-terminus and is 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 or biologically active fragments thereof, or analogs thereof having well-known substitutions and/or additions, as well as nontoxic salts of any of the foregoing, may be administered to animals, including humans, to stimulate the release of GH and may be used diagnostically.
摘要翻译：已经合成了大鼠下丘脑GRF，具有下式：H-His-Ala-Asp-Ala-Ile-Phe-Thr-Ser-Ser-Tyr-Arg-Arg-Ile-Leu-Gly-Gln-Leu-Ala -Arg-Lys-Leu-Leu-His-Glu-Ile-Met-Asn-Arg-Gln-Gln-Gly-Glu-Arg-Asn-Gln-Glu-Gln-Arg-Ser-Arg-Phe- 哦。该肽被认为是并且在下文中被称为rhGRF（对于大鼠下丘脑GH释放因子）。本发明提供了在动物中刺激垂体GH的释放非常有效的合成肽，其具有下式：H-R1-Ala-Asp-Ala-Ile-Phe-Thr-R8-Ser-R10-Arg-R12- R13-Leu-R15-Gln-Leu-R1 8-Ala-Arg-Lys-Leu-Leu-R24-R25-Ile-R27-R28-Arg-Gln-Gln-Gly-Glu-R34-Asn-Gln-Glu -R38-R39-R40-Arg-R42-R43-R44-Y，其中R1是Tyr，Met，D-Tyr，Leu，D-His或His; R8是Ser或Asn; R10是Tyr或D-Tyr; R12是Arg或Lys; R13是Ile或Val; R15是Gly或D-Ala; R18是Tyr或Ser; R24是His或Gln; R25是Glu或Asp; R27是Met，Ala，Nle，Ile，Leu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或Ala; R43是Asn或Arg; R44是天然氨基酸或des-R44; 并且Y表示C末端的氨基酸残基的羧基部分，并且是基团-COOR，-CRO，-CONHNHR，-CON（R）（R'）或-CH 2OR，其中R和R'为低级烷基氟代低级烷基或氢。这些具有众所周知的取代和/或添加的肽或其类似物或其类似物以及前述任何一种的无毒盐可以被给予动物，包括人，以刺激GH的释放，并且可以是用于诊断。

109. 发明授权

US4563352A Human pancreatic GRF 失效
标题翻译：人胰腺GRF
公开(公告)号：US4563352A
公开(公告)日：1986-01-07
申请号：US432663
申请日：1982-10-04
申请人： Jean E. F. Rivier , Joachim Spiess , Wylie W. Vale, Jr.
发明人： Jean E. F. Rivier , Joachim Spiess , Wylie W. Vale, Jr.
IPC分类号： A61K38/00 , A23K1/16 , A61K38/04 , A61K38/07 , A61K38/25 , C07C20060101 , C07K1/06 , C07K14/00 , C07K14/575 , C07K14/60 , C07K14/61 , A61K37/02
CPC分类号： C07K14/60 , A61K38/00 , Y10S530/845 , Y10S930/12
摘要： Human pancreatic GRF has been synthesized. The invention provides synthetic peptides which are extremely potent in stimulating the release of pituitary GH in mammals and which have the formula: H-Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-R.sub.15 -Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Met-Ser-Arg-Gln-Gln-Gly-Glu-Ser-Asn-Gln-Glu-Arg-Gly-R.sub.40 -R.sub.41 -R.sub.42 -Y wherein R.sub.15 is Gly or D-Ala, R.sub.40 is Ala or des-R.sub.40, R.sub.41 is Phe or des-R.sub.41, R.sub.42 is des-R.sub.42 or 1 to 8 different amino acid residues selected from the group consisting of Gln, Gly, Ile, Leu, Lys, Pro, Thr and Val, and Y signifies the carboxyl moiety of the amino acid residue at the C-terminal and is the radical -COOR.sub.1,-CR.sub.1 O,-CONHNHR.sub.1,-CON(R.sub.1)(R.sub.2) or -CH.sub.2 OR.sub.1, with R.sub.1 and R.sub.2 being lower alkyl or hydrogen. These peptides or biologically active fragments thereof, or analogs thereof having well-known substitutions and/or additions, as well as nontoxic salts of any of the foregoing, may be administered therapeutically to animals, including humans, and may be used diagnostically.
摘要翻译：人胰腺GRF已被合成。本发明提供了非常有效刺激哺乳动物垂体GH释放的合成肽，其具有下式：H-Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys- Val-Leu-R15-Gln-Leu- Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Met-Ser-Arg-Gln-Gln-Gly-Glu-Ser-Asn-Gln-Glu -Arg-Gly-R40-R41-R42-Y，其中R15是Gly或D-Ala，R40是Ala或des-R40，R41是Phe或des-R41，R42是des-R42或1到8个不同的氨基酸残基选自Gln，Gly，Ile，Leu，Lys，Pro，Thr和Val组成的组，Y表示C-末端的氨基酸残基的羧基部分，是-COOR1，-CR1O，-CONHNHR1基团，-CON（R 1）（R 2）或-CH 2 OR 1，其中R 1和R 2为低级烷基或氢。具有众所周知的取代和/或添加的这些肽或其类似物或其类似物以及前述任何一种的无毒盐可以治疗性地给予动物，包括人，并且可以在诊断上使用。

110. 发明授权

US4528190A GRF Analogs IV 失效
标题翻译： GRF类似物IV
公开(公告)号：US4528190A
公开(公告)日：1985-07-09
申请号：US611844
申请日：1984-05-18
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： C07K14/575 , A23K1/16 , A61K38/00 , A61K38/04 , A61K38/18 , A61K38/22 , A61K38/25 , A61P5/00 , C07K14/00 , C07K14/60 , C07K14/61 , C07C103/52 , A61K37/02
CPC分类号： C07K14/60 , A23K20/147 , A61K38/00 , Y10S930/12
摘要： Human GRF(hGRF), rat GRF(rGRF) porcine GRF(pGRF) and bovine GRF(bGRF) 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 -R.sub.14 -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 -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, 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, D-Ala or D-NMA; 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.14 is Leu or D-Leu; 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.29 is Arg or D-Arg; 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 any or all of the residues between R.sub.28 and R.sub.44, inclusive, may be deleted and provided also that R.sub.2 is D-NMA and/or R.sub.14 is D-Leu and/or R.sub.29 is D-Arg. These peptides as well as their nontoxic salts may also be used diagnostically.
摘要翻译：人GRF（hGRF），大鼠GRF（rGRF）猪GRF（pGRF）和牛GRF（bGRF）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-R14-R15-Gln-R17-R18-Al-Arg-Lys-Leu-R23-R24-R25-Ile-R27-R28-R29-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，D-Ala或D-NMA; 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; R14是Leu或D-Leu; R15是Gly或D-Ala; R17是Leu或D-Leu; R18是Tyr或Ser; R23为Leu或D-Leu; R24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; R29为Arg或D-Arg; 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R28和R44之间的任何或全部残基（包括端值）可以被缺失，并且还提供R2是D-NMA和/或R14是D-Leu和/或R29是D-Arg。这些肽以及它们的无毒盐也可以在诊断上使用。

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