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公开(公告)号：US4444759A
公开(公告)日：1984-04-24
申请号：US402117
申请日：1982-07-26
IPC分类号： C07K14/575 , A61K38/00 , A61K38/02 , C07K7/23 , C07C103/52 , A61K37/02
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 gondads. The peptides have the structure.X-.beta.-D-2NAL-R.sub.2 -D-Trp-Ser-R.sub.5 -R.sub.6 -R.sub.7 -Arg-Pro-R.sub.10 wherein X is hydrogen or an acyl group having 7 or less carbon atoms; R.sub.2 is Cl-D-Phe, F-D-Phe, NO.sub.2 -D-Phe, Cl.sub.2 -D-Phe or Br-D-Phe; R.sub.5 is Tyr or Cl-Phe; R.sub.6 is 4-NH.sub.2 -D-Phe or D-Arg; R.sub.7 is Leu or N.alpha.Me-Leu; and R.sub.10 is Gly-NH.sub.2, NHCH.sub.2 CH.sub.3 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。 有效量的施用可阻止雌性哺乳动物卵的排卵和/或由金字塔释放类固醇。 肽具有结构。 X-β-D-2NAL-R2-D-Trp-Ser-R5-R6-R7-Arg-Pro-R10其中X是氢或具有7个或更少碳原子的酰基; R2是Cl-D-Phe，F-D-Phe，NO2-D-Phe，Cl2-D-Phe或Br-D-Phe; R5是Tyr或Cl-Phe; R6是4-NH2-D-Phe或D-Arg; R7是Leu或NαMe-Leu; 并且R 10是Gly-NH 2，NHCH 2 CH 3或D-Ala-NH 2。
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公开(公告)号：US4415558A
公开(公告)日：1983-11-15
申请号：US378999
申请日：1982-05-17
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。
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公开(公告)号：US4410514A
公开(公告)日：1983-10-18
申请号：US447091
申请日：1982-12-06
IPC分类号： C07K7/06 , C07K7/23 , C07K14/575 , C07C103/52 , A61K37/02
CPC分类号： C07K7/23 , Y10S514/80 , Y10S930/13
摘要： Peptides for promoting the spawning of fish having the formula:pGlu--His--Trp--Ser--Tyr--R.sub.6 --Trp--Leu--Pro--R.sub.10 --NHRor a nontoxic salt thereof, wherein R.sub.6 is a D-isomer of an .alpha.-amino acid selected from the group consisting ofTrp, Ala, Phe, Lys, Pro, Met, Leu, Glu, Asn, Arg, Tyr, Cys, His, Chg, Nva, Orn, Thr, Abu, Phg, Ile, Glu, Asp, Nle and Val and wherein R.sub.10 is Gly or des-R.sub.10 and R is H or C.sub.n Y.sub.2n CY.sub.3, with Y being H or F and n being 0, 1, 2 or 3, provided that when R.sub.10 is des-R.sub.10, n is not 0. The D-isomer .alpha.-amino acids may contain known substitutions.
摘要翻译： 用于促进产生具有下式的鱼的肽：pGlu-His-Trp-Ser-Tyr-R6-Trp-Leu-Pro-R10-NHR或其无毒盐，其中R6是α-氨基的D-异构体 选自Trp，Ala，Phe，Lys，Pro，Met，Leu，Glu，Asn，Arg，Tyr，Cys，His，Chg，Nva，Orn，Thr，Abu，Phg，Ile，Glu，Asp ，Nle和Val，其中R10为Gly或des-R10，R为H或CnY2nCY3，Y为H或F，n为0,1,2或3，条件是当R10为des-R10时，n不为0 D-异构体α-氨基酸可以含有已知的取代基。
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公开(公告)号：US4244946A
公开(公告)日：1981-01-13
申请号：US47026
申请日：1979-06-11
IPC分类号： A61K38/04 , A61K38/00 , A61P5/00 , A61P15/00 , C07K7/23 , C07K14/575 , A61K37/00 , C07C103/52
CPC分类号： C07K7/23 , A61K38/00 , Y10S514/80 , Y10S930/13
摘要： [im-Bzl D-His.sup.6 ]LRF and [D-His.sup.6 (im-Bzl), Pro.sup.9 -NEt]LRF exhibit hydrophillicity comparable to that of LRF and act as superagonists exhibiting potencies, respectively, about 12 and more than 200 times 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.
摘要翻译： [im-Bzl D-His6] LRF和[D-His6（im-Bzl），Pro9-NEt] LRF表现出与LRF相当的亲水性，并且作为显示效力的超级拮抗剂分别为约12倍和超过200倍 LRF。 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。
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公开(公告)号：US4215038A
公开(公告)日：1980-07-29
申请号：US950301
申请日：1978-10-16
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。
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公开(公告)号：US5530095A
公开(公告)日：1996-06-25
申请号：US447613
申请日：1995-05-23
申请人： Joan Vaughn , Wolfgang H. Fischer , Jean E. F. Rivier , Jean-Louis M. Nahon , Francoise G. Presse , Wylie W. Vale, Jr.
发明人： Joan Vaughn , Wolfgang H. Fischer , Jean E. F. Rivier , Jean-Louis M. Nahon , Francoise G. Presse , Wylie W. Vale, Jr.
IPC分类号： C12N15/09 , A61K38/00 , A61K38/04 , A61P35/00 , C07K7/06 , C07K7/08 , C07K7/64 , C07K14/00 , C07K14/575 , C12N15/12 , C12N15/16 , C12P21/02
CPC分类号： C07K7/08 , C07K7/64 , A61K38/00 , Y10S530/827 , Y10S530/854
摘要： Mammalian melanin-concentrating hormone (MCH) is isolated from rat tissue, purified and characterized. These MCH peptides are useful for treating skin disorders, for suppressing the proliferation of skin tumor cells, such as melanomas in mammals, and for modulating the secretion of ACTH. Generally, peptides are provided which have the following formula: ##STR1## or which are naturally occurring homologs of the peptide with said formula. The peptides which are the naturally occurring MCH homologs of mammalian species other than rat can also be obtained using the materials disclosed, as demonstrated specifically with human MCH, which is found to have the same structure as rat MCH. Also disclosed are the amino acid sequences of, and the nucleotide sequences of the cDNAs which encode, the putative precursors of rat MCH and human MCH. These precursors may also include one or more biologically active peptides N-terminally of the mature MCH's. Among these peptides, which are thought to be formed from the MCH precursors, are the peptide with the sequence H-Glu-Ile-Gly-Asp-Glu-Glu-Asn-Ser-Ala-Lys-Phe-Pro-Ile-NH.sub.2, which is cross-reactive with antibodies against alpha-MSH and CRF, and the peptide with the sequence H-Gly-X.sub.NGE -Phe-Pro-Ala-Glu-Asn-Gly-Val-Gln-Asn-Thr-Glu-Ser-Thr-Gln-Glu-OH, wherein X.sub.NGE is Pro-Ala-Val or Ser-Val-Ala, which is cross-reactive with antibodies against GRF.
摘要翻译： 从大鼠组织中分离哺乳动物黑色素浓缩激素（MCH），进行纯化和表征。 这些MCH肽可用于治疗皮肤病症，抑制皮肤肿瘤细胞增殖，如哺乳动物的黑素瘤，以及调节ACTH的分泌。 通常，提供具有下式的肽：＆lt; IMAGE＆gt;或具有所述式的肽的天然存在同系物。 作为除大鼠之外的哺乳动物物种的天然存在的MCH同源物的肽也可以使用公开的材料获得，如用人MCH特异性证实的，其被发现具有与大鼠MCH相同的结构。 还公开了编码大鼠MCH和人MCH的推定前体的cDNA的氨基酸序列和cDNA的核苷酸序列。 这些前体还可以包括成熟MCH的N-末端的一种或多种生物活性肽。 在这些被认为由MCH前体形成的肽中，具有序列H-Glu-Ile-Gly-Asp-Glu-Glu-Asn-Ser-Ala-Lys-Phe-Pro-Ile-NH 2的肽 ，其与抗α-MSH和CRF的抗体具有交叉反应性，并且具有序列H-Gly-XNGE-Phe-Pro-Ala-Glu-Asn-Gly-Val-Gln-Asn-Thr-Glu-Ser -Thr-Gln-Glu-OH，其中XNGE是Pro-Ala-Val或Ser-Val-Ala，其与抗GRF的抗体交叉反应。
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公开(公告)号：US5278146A
公开(公告)日：1994-01-11
申请号：US905564
申请日：1992-06-29
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。
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公开(公告)号：US5132111A
公开(公告)日：1992-07-21
申请号：US508258
申请日：1990-04-11
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。
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公开(公告)号：US5112809A
公开(公告)日：1992-05-12
申请号：US615838
申请日：1990-11-20
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。
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公开(公告)号：US4728726A
公开(公告)日：1988-03-01
申请号：US939342
申请日：1986-12-08
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。
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