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公开(公告)号：US5049655A
公开(公告)日：1991-09-17
申请号：US326984
申请日：1989-03-22
申请人： Joan Vaughan , Wolfgang H. Fischer , Jean E. F. Rivier , Jean-Louis M. Nahon , Francoise G. Presse , Wylie W. Vale, Jr.
发明人： Joan Vaughan , 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
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：US4737578A
公开(公告)日：1988-04-12
申请号：US848924
申请日：1986-04-07
申请人： Ronald M. Evans , Michael G. Rosenfeld , Gail Cerelli , Kelly E. Mayo , Joachim Spiess , Jean E. F. Rivier , Wylie W. Vale, Jr.
发明人： Ronald M. Evans , Michael G. Rosenfeld , Gail Cerelli , Kelly E. Mayo , Joachim Spiess , Jean E. F. Rivier , Wylie W. Vale, Jr.
IPC分类号： A61K38/00 , C07K14/575 , C07K7/10 , C07K13/00
CPC分类号： C07K14/575 , A61K38/00 , Y10S930/26
摘要： Proteins with inhibin activity having a weight of about 32,000 daltons. The molecule is composed of two chains having molecular weights of about 18,000 and about 14,000 daltons, respectively, which are bound together by disulfide bonding. The 18K chain is obtained from the human inhibin gene and has the formula: H-Ser-Thr-Pro-Leu-Met-Ser-Trp-Pro-Trp-Ser-Pro-Ser-Ala-Leu-Arg-Leu-Leu-Gln-Arg-Pro-Pro-Glu-Glu-Pro-Ala-Ala-His-Ala-Asn-Cys-His-Arg-Val-Ala-Leu-Asn-Ile-Ser-Phe-Gln-Glu-Leu-Gly-Trp-Glu-Arg-Trp-Ile-Val-Tyr-Pro-Pro-Ser-Phe-R.sub.65 -Phe-His-Tyr-Cys-His-Gly-Gly-Cys-Gly-Leu-His-Ile-Pro-Pro-Asn-Leu-Ser-Leu-Pro-Val-Pro-Gly-Ala-Pro-Pro-Thr-Pro-Ala-Gln-Pro-Tyr-Ser-Leu-Leu-Pro-Gly-Ala-Gln-Pro-Cys-Cys-Ala-Ala-Leu-Pro-Gly-Thr-Met-Arg-Pro-Leu-His-Val-Arg-Thr-Thr-Ser-Asp-Gly-Gly-Tyr-Ser-P e-Lys-Tyr-Glu-Thr-Val-Pro-Asn-Leu-Leu-Thr-Gln-His-Cys-Ala-Cys-Ile-OH, wherein R.sub.65 is Ile or Arg. The 18K chain is connected by disulfide bonding to the 14K chain.
摘要翻译： 具有约32,000道尔顿重量的具有抑制素活性的蛋白质。 该分子由分子量分别为约18,000和约14,000道尔顿的两条链组成，它们通过二硫键结合在一起。 18K链由人抑制素基因得到，具有下式：H-Ser-Thr-Pro-Leu-Met-Ser-Trp-Pro-Trp-Ser-Pro-Ser-Ala-Leu-Arg-Leu-Leu Gln-Arg-Pro-Pro-Glu-Glu-Pro-Ala-Ala-His-Ala-Asn-Cys-His-Arg-Val-Ala-Le-Asn-Ile-Ser-Phe-Gln-Glu- Leu-Gly-Trp-Glu-Arg-Trp-Ile-Val-Tyr-Pro-Pro-Ser-Phe-R65-Phe-His-Tyr-Cys-His-Gly-Gly-Cys-Gly-Leu-His- Ile-Pro-Pro-As n-Leu-Ser-Leu-Pro-Val-Pro-Gly-Ala-Pro-Pro-Thr-Pro-Ala-Gln-Pro-Tyr-Ser-Leu-Leu-Pro-Gly -Ala-Gln-Pro-Cys-Cys-Ala-Ala-Leu-Pro-Gly-Thr-Met-Arg-Pr-Leu-His-Val-Arg-Thr-Thr-Ser-Asp-Gly-Gly- Tyr-Ser-P e-Lys-Tyr-Glu-Thr-Val-Pro-Asn-Leu-Leu-Thr-Gln-His-Cys-Ala-Cys-Ile-OH，其中R65是Ile或Arg。 18K链通过二硫键与14K链连接。
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公开(公告)号：US4677193A
公开(公告)日：1987-06-30
申请号：US704299
申请日：1985-02-22
IPC分类号： A61K38/04 , A61K38/00 , A61K38/22 , A61P5/00 , C07K1/113 , C07K7/06 , C07K7/23 , C07K14/00 , C07K14/575 , C07K7/20
CPC分类号： C07K7/23 , A61K38/00 , Y10S930/13
摘要： GnRH peptide analogs which regulate the secretion of gonadotropins by the pituitary gland and either promote or inhibit the release of steroids by the gonads. Administration of an effective amount of a GnRH antagonist prevents ovulation of female mammalian eggs and/or the release of gonadotropins. Administration of GnRH agonists can be used to regulate fertility in male and female mammals.These and other peptide hormones exhibit improved binding efficiency and biological potency as a result having a residue in a critical, generally central location in the chain which residue contains a mixed alkyl ketone side-chain terminating in an aromatic group. Methods for efficiently synthesizing these peptides from readily available compounds are disclosed.
摘要翻译： GnRH肽类似物，其调节垂体分泌促性腺激素并促进或抑制性腺释放类固醇。 施用有效量的GnRH拮抗剂可防止雌性哺乳动物卵的排卵和/或释放促性腺激素。 GnRH激动剂的施用可用于调节雄性和雌性哺乳动物的生育力。 这些和其它肽激素表现出改善的结合效率和生物效力，因此在链中的关键的，通常中心的位置具有残基，残基含有终止于芳族基团的混合烷基酮侧链。 公开了从容易获得的化合物有效地合成这些肽的方法。
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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。
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公开(公告)号：US4594329A
公开(公告)日：1986-06-10
申请号：US610110
申请日：1984-05-14
IPC分类号： A61K38/00 , C07K14/575 , C07K7/00 , A61K37/02
CPC分类号： C07K14/57509 , A61K38/00 , Y10S436/817
摘要： Analogs of rCRF and oCRF 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 potent is: H-Ser-Gln-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Phe-His-Leu-Leu-Arg-Glu-Met-Leu-Glu-Met-Ala-Lys-Ala-Glu-Gln-Glu-Ala-Glu-Gln-Ala-Ala-Leu-Asn-Arg-Leu-Leu-Leu-Glu-Glu-Ala-NH.sub.2. In the analogs, 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 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 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rCRF和oCRF的类似物，其可被施用以实现ACTH，β-内啡肽，β-促肌动蛋白，前 - 肌动蛋白皮质素基因的其他产物和皮质酮水平的显着升高和/或延长期间的血压降低 的时间。 已经发现特别有效的一种类似物是：H-Ser-Gln-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Phe-His-Leu-Leu-Arg-Glu- Leu-Glu-Met-Ala-Lys-Ala-Glu-Gln-Glu-Ala-Glu-Gln-Ala-Ala-Leu-Asn -Arg-Leu-Leu-Leu-Glu-Glu-Ala-NH2。 在类似物中，前五个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：US4529595A
公开(公告)日：1985-07-16
申请号：US457862
申请日：1983-01-13
CPC分类号： C07K14/60 , A23K20/147 , A61K38/00 , Y10S930/12
摘要： Human pancreatic GRF analogs which are extremely potent in stimulating the release of pituitary GH in mammals and which have the formula: H-R-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-R.sub.27 -Ser-Arg-Gln-Gln-Gly-Glu-Ser-Asn-Gln-Glu-Arg-Gly-Ala-Y wherein R is selected from the D- and L-isomers of Tyr, Phe and His, R.sub.15 is Gly or D-Ala, R.sub.27 is selected from the group consisting of the D- and L-isomers of Ala, Nle, Ile, Leu, Met 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, provided that when R is Tyr, R.sub.27 is other than Met. Phe may be substituted for Tyr in the 10-position, and D-Ala may be substituted for Gly in the 28-position. These peptides or biologically active fragments thereof, which will generally extend from the N-terminal to the vicinity of a residue between positions 27 and 32, 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类似物在刺激哺乳动物垂体GH的释放方面非常有效，具有以下分子式：HR-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu -R15-Gln-Leu-Se-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-R27-Ser-Arg-Gln-Gln-Gly-Glu-Ser-Asn-Gln-Glu-Arg- Gly-Ala-Y其中R选自Tyr，Phe和His的D-和L-异构体，R15是Gly或D-Ala，R27选自Ala， Nle，Ile，Leu，Met和Val，Y表示C-末端的氨基酸残基的羧基部分，是-COOR1，-CR1O，-CONHNHR1，-CON（R1）（R2）或-CH2OR1 其中R1和R2是低级烷基或氢，条件是当R为Tyr时，R27不是Met。 Phe可以取代10位的Tyr，D-Ala可以取代28位的Gly。 这些肽或其生物活性片段通常从N末端延伸至位置27和32之间的残基，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。
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公开(公告)号：US4443368A
公开(公告)日：1984-04-17
申请号：US437949
申请日：1982-11-01
申请人： Nancy M. Sherwood , Lee E. Eiden , Michael J. Brownstein , Joachim Spiess , Jean E. F. Rivier , Wylie W. Vale, Jr.
发明人： Nancy M. Sherwood , Lee E. Eiden , Michael J. Brownstein , Joachim Spiess , Jean E. F. Rivier , Wylie W. Vale, Jr.
IPC分类号： A61K38/00 , C07K7/23 , C07C103/52
CPC分类号： C07K7/23 , A61K38/00 , Y10S930/13
摘要： The peptide having the following formula has a potent effect on the reproduction processes of fish and is termed Fish GnRH:pGlu-His-Trp-Ser-Tyr-Gly-Trp-Leu-Pro-Gly-NH.sub.2.Spawning of teleostei fish can be promoted by administration of effective amounts of the peptide.
摘要翻译： 具有下式的肽对鱼的繁殖过程具有有效的作用，被称为鱼GnRH：pGlu-His-Trp-Ser-Tyr-Gly-Trp-Leu-Pro-Gly-NH2。 可以通过施用有效量的肽来促进远端鱼的产生。
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公开(公告)号：US4386074A
公开(公告)日：1983-05-31
申请号：US287189
申请日：1981-07-27
IPC分类号： A61K38/00 , C07K7/16 , C07K7/23 , A61K37/00 , C07C103/52
CPC分类号： C07K7/16 , 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:R.sub.1 -dehydro Pro-R.sub.2 -D-Trp-Ser-Tyr-D-Trp-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 dichloro-D-Phe, C.sup..alpha. Me4Cl-D-Phe, (CH.sub.3).sub.5 -D-Phe, CF.sub.3 -D-Phe, F-D-Phe, difluoro-D-Phe, AcNH-D-Phe, NO.sub.2 -D-Phe, dinitro-D-Phe, Br-D-Phe, dibromo-D-Phe, CH.sub.3 S-D-Phe, OCH.sub.3 -D-Phe and CH.sub.3 -D-Phe, wherein any D-isomer amino acid can be substituted for D-Trp in the 6-position, and wherein N.sup..alpha. MeLeu may be substituted for Leu.
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-脱氢Pro-R2-D-Trp-Ser-Tyr-D-Trp-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选自二氯-D-Phe，CαMe4Cl-D-Phe，（CH3）5-D-Phe，CF3-D-Phe，FD-Phe，二氟-D-Phe，AcNH-D- Phe，NO 2 -D-Phe，二硝基-D-Phe，Br-D-Phe，二溴-D-Phe，CH3S-D-Phe，OCH3-D-Phe和CH3-D-Phe，其中任何D-异构体氨基 酸可以代替6位的D-Trp，并且其中NαMeLeu可以代替Leu。
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公开(公告)号：US4307083A
公开(公告)日：1981-12-22
申请号：US147555
申请日：1980-05-08
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。
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公开(公告)号：US4292313A
公开(公告)日：1981-09-29
申请号：US140487
申请日：1980-04-15
IPC分类号： A61K38/04 , A61K38/00 , A61P13/02 , A61P15/00 , C07K7/16 , C07K7/23 , C07K14/575 , A61K37/00 , C07C103/52
CPC分类号： C07K7/16 , C07K7/23 , A61K38/00 , Y10S514/809 , 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 -pCl-D-Phe-D-Trp-Ser-Tyr-R.sub.3 -R.sub.4 -Arg-Pro-R.sub.5wherein 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 D-Trp and (imBzl)D-His; R.sub.4 is selected from the group consisting of Leu and N.sup..alpha. MeLeu; and R.sub.5 is selected from the group consisting of Gly-NH.sub.2 and NHCH.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-pCl-D-Phe-D-Trp-Ser-Tyr-R3-R4-Arg-Pro-R5，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D-Trp和（imBz1）D-His; R4选自Leu和NαMeLeu; 并且R 5选自Gly-NH 2和NHCH 2 CH 3。
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