公开(公告)号：US07238775B2

公开(公告)日：2007-07-03

申请号：US11041676

申请日：2005-01-24

申请人： Jean E. F. Rivier ,  Jean Claude Reubi ,  Judit Erchegyi ,  Roland Riek

发明人： Jean E. F. Rivier ,  Jean Claude Reubi ,  Judit Erchegyi ,  Roland Riek

IPC分类号： A61K38/00

CPC分类号： C07K14/655 ,  A61K38/00

摘要： Analogs of SRIF which are selective for SSTR4 in contrast to the other cloned SRIF receptors are useful in determining tissue and cellular expression of the receptor SSTR4 and its biological role in regulating tumor growth. SRIF analog peptides, such as des-AA1,2,4,5,12,13[Ala7]-SRIF; des-AA1,2,4,5,12,13[Aph7]-SRIF, des-AA1,2,4,5,12,13[Aph7]Cbm-SRIF; des-AA1,2,4,5,12,13[Tyr2,Ala7]-Cbm-SRIF, and des-AA1,2,4,5,12,13[Tyr7,CβMe-L-2Nal8]-SRIF, and counterparts incorporating D-Cys3 and/or D-Trp8 and/or Ala11, bind with high affinity to the cloned human receptor SSTR4 and activate the receptor, but they do not bind with significant affinity to human SSTR1, SSTR2, SSTR3 or SSTR5. By incorporating an iodinated tyrosine in position-2 in these SSTR4-selective SRIF analogs, a labeled compound useful in drug-screening methods is provided. Alternatively, for use in therapy, cytotoxins or highly radioactive elements can be N-terminally coupled or complexed thereto.

摘要翻译： 与其他克隆的SRIF受体相比，选择性SSTR4的SRIF的类似物可用于确定受体SSTR4的组织和细胞表达及其在调节肿瘤生长中的生物学作用。 SRIF类似物肽，例如des-AA 1,2,4,5,12,13，[Ala 7] -SRIF; des-AA 1,2,4,5,12,13 [Aph7] -SRIF，des-AA 1,2,4,5,12 ，13β-Cpm-SRIF; des-AA 1,2,4,5,12,13 [Tyr2]，Ala7-Cbm-SRIF，和des- AA 1,2,4,5,12,13 [Tyr 7]，C 2 H 2 Me-L-2Nal 8， SUP]] - SRIF，以及掺有D-Cys 3和/或D-Trp 8和/或Ala 11的对应物与高结合 对克隆的人受体SSTR4的亲和力并激活受体，但它们不以与人SSTR1，SSTR2，SSTR3或SSTR5的显着亲和力结合。 通过在这些SSTR4选择性SRIF类似物中加入位置2的碘化酪氨酸，可以提供用于药物筛选方法的标记化合物。 或者，为了用于治疗，细胞毒素或高度放射性元素可以是N-末端偶联或与其复合的。

公开(公告)号：US06747125B1

公开(公告)日：2004-06-08

申请号：US08727798

申请日：1996-10-07

申请人： Carl A. Hoeger ,  Jean E. F. Rivier ,  Paula Guess Theobald ,  John S. Porter

发明人： Carl A. Hoeger ,  Jean E. F. Rivier ,  Paula Guess Theobald ,  John S. Porter

IPC分类号： C07K1600

CPC分类号： C07D249/14 ,  A61K38/00 ,  C07C277/08 ,  C07C279/28 ,  C07K1/006 ,  C07K7/23 ,  Y10S514/80 ,  Y10S930/11 ,  Y10S930/13

摘要： Peptides which include unnatural amino acids and which either promote or 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 peptides that are GnRH antagonists prevents ovulation of female mammalian eggs and/or the release of steroids by the gonads and may be used to treat steroid-dependent tumors. The agonists can be used for control of reproduction processes, to treat precocious puberty, endometriosis, and the like. 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. Unnatural amino acids having the following formula are incorporated in a preferred group of synthesized peptides:

摘要翻译： 包括非天然氨基酸并且促进或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，并可用于治疗类固醇依赖性肿瘤。 激动剂可用于控制繁殖过程，治疗早熟青春期，子宫内膜异位症等。 肽是十肽GnRH的类似物，其中在3-，5-，6-和/或8-位有至少一个非天然氨基酸残基。 具有下列结构式的非天然氨基酸被掺入优选的一组合成肽中：

公开(公告)号：US5874227A

公开(公告)日：1999-02-23

申请号：US556578

申请日：1995-11-10

申请人： Jean E. F. Rivier

发明人： Jean E. F. Rivier

IPC分类号： G01N33/15 ,  A61K38/00 ,  A61K38/04 ,  A61K45/00 ,  A61P25/00 ,  A61P29/00 ,  A61P35/00 ,  C07K14/575 ,  G01N33/50 ,  G01N33/566 ,  G01N33/68 ,  G01N33/74 ,  G01N33/53 ,  A61K38/12 ,  A61K38/28 ,  C07K5/00

CPC分类号： G01N33/5008 ,  C07K14/57509 ,  G01N33/502 ,  G01N33/566 ,  G01N33/68 ,  G01N33/6842 ,  G01N33/74 ,  A61K38/00 ,  G01N2333/5751 ,  Y10S514/805 ,  Y10S930/26

摘要： Novel cyclic CRF antagonist peptides have the amino acid sequence: ##STR1## wherein Y is Ac, H, Ac-Thr or H-Thr; R.sub.30 is Glu or Cys; R.sub.32 is His or preferably a basic and/or aromatic D-amino acid such as D-His or D-Arg; R.sub.33 is Lys, Orn or Cys. The N-terminus may be extended by Leu or Asp-Leu. CML may be substituted for Leu.sup.27, and D-Tyr may be substituted for D-Phe to facilitate labelling. Lys may be substituted for Arg.sup.23, and its side chain connected by a lactam bridge to Glu.sup.20 to form a bicyclic peptide. Disclosed CRF antagonists include:(cyclo 30-33)�D-Phe.sup.12, Nle.sup.21,38, Glu.sup.30, Lys.sup.33 !r/hCRF(12-41),(cyclo 30-33)�Ac-Thr.sup.11, D-Phe.sup.12, Nle.sup.21,38, Glu.sup.30, Lys.sup.33 !r/hCRF(11-41),(cyclo 30-33)�D-Phe.sup.12, Nle.sup.21,38, Cys.sup.30,33 !r/hCRF(12-41),(bicyclo 20-23,30-33)�D-Phe.sup.12, Nle.sup.21,38, Lys.sup.23,33, Glu.sup.30 !-r/hCRF(12-41),(cyclo 30-33)�D-Phe.sup.12, Nle.sup.21,38, Glu.sup.30, D-His.sup.32, Lys.sup.33 !r/hCRF(12-41),(cyclo 30-30)�D-Phe.sup.12, Nle.sup.21,38, CML.sup.27, Glu.sup.30, D-His.sup.32, Lys.sup.33 !r/hCRF(12-41) and(cyclo 30-30)�D-Phe.sup.12, Nle.sup.21,38, Glu.sup.30, D-Arg.sup.32, Lys.sup.33 !r/hCRF(12-41).Labelled antagonists such as (cyclo 30-30)�I.sup.125 D-Tyr.sup.12, Nle.sup.21,38, Glu.sup.30, D-His.sup.32, Lys.sup.33 !r/hCRF(12-41) are useful in drug screening assays.

摘要翻译： 新型循环CRF拮抗剂肽具有氨基酸序列：其中Y是Ac，H，Ac-Thr或H-Thr; R30是Glu或Cys; R32是His或优选碱性和/或芳族D-氨基酸，例如D-His或D-Arg; R33是Lys，Orn或Cys。 N末端可以被Leu或Asp-Leu延伸。 CML可以代替Leu27，并且D-Tyr可以被D-Phe取代以便于标记。 Lys可以代替Arg23，其侧链通过内酰胺桥连接至Glu20以形成双环肽。 公开的CRF拮抗剂包括：（环30-33）[D-Phe12，Nle21,38，Glu30，Lys33] r / hCRF（12-41），（环30-33）[Ac-Thr11，D-Phe12，Nle21， 38，Glu30，Lys33] r / hCRF（11-41），（环30-33）[D-Phe12，Nle21,38，Cys30,33] r / hCRF（12-41），（双环20-23,30 -33）[D-Phe12，Nle21,38，Lys23,33，Glu30] -r / hCRF（12-41），（环30-33）[D-Phe12，Nle21,38，Glu30，D-His32，Lys33 ] r / hCRF（12-41），（环30-30）[D-Phe12，Nle21,38，CML27，Glu30，D-His32，Lys33] r / hCRF（12-41）和（环30-30） [D-Phe12，Nle21,38，Glu30，D-Arg32，Lys33] r / hCRF（12-41）。 标记的拮抗剂如（环30-30）[I125D-Tyr12，Nle21,38，Glu30，D-His32，Lys33] r / hCRF（12-41）可用于药物筛选测定。

公开(公告)号：US5844074A

公开(公告)日：1998-12-01

申请号：US575148

申请日：1995-12-19

申请人： Jean E. F. Rivier

发明人： Jean E. F. Rivier

IPC分类号： G01N33/15 ,  A61K38/00 ,  A61K38/04 ,  A61K45/00 ,  A61P25/00 ,  A61P29/00 ,  A61P35/00 ,  C07K14/575 ,  G01N33/50 ,  G01N33/566 ,  G01N33/68 ,  G01N33/74 ,  A61K38/28 ,  A61K38/12 ,  C07K7/64 ,  C07K14/695

CPC分类号： G01N33/5008 ,  C07K14/57509 ,  G01N33/502 ,  G01N33/566 ,  G01N33/68 ,  G01N33/6842 ,  G01N33/74 ,  A61K38/00 ,  G01N2333/5751 ,  Y10S514/805 ,  Y10S930/26

摘要： Novel cyclic CRF agonist peptides have the amino acid sequence: (cyclo 30-33)Ac-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-D-Phe-His-Leu-Leu-Arg-Glu-Val-Leu-Glu-Nle-Ala-Arg-Ala-Glu-Gln-Leu-Ala-Gln-R.sub.30 -Ala-R.sub.32 -R.sub.33 -Asn-Arg-Lys-Leu-Nle-Glu-Ile-Ile-NH.sub.2 wherein R.sub.30 is Glu or Cys; R.sub.32 is His or a D-amino acid such as D-His, D-Arg or similar; R.sub.33 is Lys, Orn or Cys. The N-terminus may be extended by Ser-Glu-Glu. Lys may be substituted for Arg.sup.23, and its side chain connected by a lactam bridge to Glu.sup.20 to form a bicyclic peptide. Certain disclosed CRF agonists include: (cyclo 30-33)�Ac-Pro.sup.4, D-Phe.sup.12, Nle.sup.21,38, D-His.sup.32, Glu.sup.30, Lys.sup.33 !r/hCRF(4-41), (cyclo 30-33)�Ac-Pro.sup.4, D-Phe.sup.12, Nle.sup.21,38, D-His.sup.32, Glu.sup.30, Orn.sup.33 !r/hCRF(4-41), (cyclo 30-33)�Ac-Pro.sup.4, D-Phe.sup.12, Nle.sup.21,38, Cys.sup.30,33, D-His.sup.32 !r/hCRF(4-41), (bicyclo 20-23,30-33)�Ac-Pro.sup.4, D-Phe.sup.12, Nle.sup.21,38, Lys.sup.23,33, Glu.sup.30, D-His.sup.32 !-r/hCRF(4-41), (cyclo 30-33)�Ac-Pro.sup.4, D-Phe.sup.12, Nle.sup.21,38, CML.sup.27, Glu.sup.30, imBzlD-His.sup.32, Lys.sup.33 !r/hCRF(4-41) and (cyclo 30-33)�Ac-Pro.sup.4, D-Phe.sup.12, Nle.sup.21,38, Glu.sup.30, D-Arg.sup.32, Lys.sup.33 !r/hCRF(4-41). Labelled agonists such as (cyclo 30-33)�I.sup.125 Tyr.sup.o, D-Phe.sup.12, Nle.sup.21,38, Glu.sup.30, D-His.sup.32, Lys.sup.33 !r/hCRF and (cyclo 30-33)�I.sup.125 D-Tyr.sup.3, D-Phe.sup.12, Nle.sup.21,38, Glu.sup.30, D-His.sup.32, Lys.sup.33 !r/hCRF(3-41) are useful in screening for more potent agonists.

摘要翻译： 新型循环CRF激动剂肽具有氨基酸序列：（环30-33）Ac-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-D-Phe-His-Leu-Leu-Arg-Glu-Val -Leu-Glu-Nle-Ala-Arg-Ala-Glu-Gln-Leu-Ala-Gln-R30-Ala-R32-R33-Asn-Arg-Lys-Leu-Nle-Glu-Ile-Ile-NH2 是Glu或Cys; R32是His或D-氨基酸，例如D-His，D-Arg或类似物; R33是Lys，Orn或Cys。 N末端可以被Ser-Glu-Glu延伸。 Lys可以代替Arg23，其侧链通过内酰胺桥连接至Glu20以形成双环肽。 某些公开的CRF激动剂包括：（环30-33）[Ac-Pro4，D-Phe12，Nle21,38，D-H​​is32，Glu30，Lys33] r / hCRF（4-41），（环30-33）[Ac -Pro4，D-Phe12，Nle21,38，D-H​​is32，Glu30，Orn33] r / hCRF（4-41），（环30-33）[Ac-Pro4，D-Phe12，Nle21,38，Cys30,33 ，D-His32] r / hCRF（4-41），（双环20-23,30-33）[Ac-Pro4，D-Phe12，Nle21,38，Lys23,33，Glu30，D-His32] -r / hCRF（4-41），（环30-33）[Ac-Pro4，D-Phe12，Nle21,38，CML27，Glu30，imBzlD-His32，Lys33] r / hCRF（4-41）和（环30-33 ）[Ac-Pro4，D-Phe12，Nle21,38，Glu30，D-Arg32，Lys33] r / hCRF（4-41）。 标记的激动剂如（环30-33）[I125Tyro，D-Phe12，Nle21,38，Glu30，D-His32，Lys33] r / hCRF和（环30-33）[I125D-Tyr3，D-Phe12，Nle21， 38，Glu30，D-His32，Lys33] r / hCRF（3-41）可用于筛选更有效的激动剂。

公开(公告)号：US5432155A

公开(公告)日：1995-07-11

申请号：US84848

申请日：1993-06-29

申请人： Baldomero M. Olivera ,  Jean E. F. Rivier ,  Lourdes J. Cruz ,  Fe Abogadie ,  Chris E. Hopkins ,  John Dykert ,  Josep L. Torres

发明人： Baldomero M. Olivera ,  Jean E. F. Rivier ,  Lourdes J. Cruz ,  Fe Abogadie ,  Chris E. Hopkins ,  John Dykert ,  Josep L. Torres

IPC分类号： A61K38/00 ,  A61K39/00 ,  A61P21/00 ,  C07K14/435 ,  C12N15/12 ,  C07K7/08 ,  A61K38/10 ,  A61K38/17

CPC分类号： C07K14/43504 ,  C07K14/435 ,  A61K38/00 ,  A61K39/00

摘要： Substantially pure conotoxins are provided which inhibit synaptic transmissions at the neuromuscular junctions and which are useful both in vivo and in assays because they specifically target particular receptors, such as the acetylcholine receptor, and ion channels. The peptides are of such length that they can be made by chemical synthesis. They also may be made using recombinant DNA techniques, and the DNA encoding such conotoxins having pesticidal properties can be incorporated as plant defense genes into plant species of interest.

摘要翻译： 提供基本上纯的芋螺毒素，其抑制神经肌肉接头处的突触传递，并且其在体内和分析中都是有用的，因为它们特异性靶向特定受体，例如乙酰胆碱受体和离子通道。 肽的长度可以通过化学合成制成。 它们也可以使用重组DNA技术制备，并且编码具有杀虫性质的这种芋螺毒素的DNA可以作为植物防御基因并入感兴趣的植物物种中。

公开(公告)号：US5352796A

公开(公告)日：1994-10-04

申请号：US78965

申请日：1993-06-17

申请人： Carl A. Hoeger ,  Jean E. F. Rivier ,  John S. Porter

发明人： Carl A. Hoeger ,  Jean E. F. Rivier ,  John S. Porter

IPC分类号： A61K38/04 ,  A61K38/00 ,  C07C277/08 ,  C07C279/18 ,  C07C279/24 ,  C07C279/28 ,  C07C313/30 ,  C07D249/14 ,  C07K1/00 ,  C07K7/02 ,  C07K7/06 ,  C07K7/23

CPC分类号： C07C279/24 ,  C07C277/08 ,  C07C279/28 ,  C07C313/30 ,  C07D249/14 ,  C07K1/006 ,  C07K7/02 ,  C07K7/23 ,  A61K38/00 ,  C07C2101/14 ,  Y02P20/55

摘要： Unnatural amino acids are provided which can be incorporated into peptides which either inhibit or promote the secretion of gonadotropins by the pituitary gland and inhibit the release of steroids by the gonads. These unnatural amino acids are useful in the synthesis of peptides and have the formula (a): ##STR1## where W is (CH.sub.2).sub.n or ##STR2## n is an integer from 1 to 6; j=1,2 or 3, and preferably, Y is N--CN, X is NH and R.sub.2 is alkyl, modified alkyl, alkenyl, alkynyl, aryl or methyl pyridyl; or the formula (b): ##STR3## where R.sub.11 is H or acyl and W is as defined in (a), and preferably R.sub.11 is H and W is ##STR4## Disclosed are peptides that 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.

摘要翻译： 可以提供非天然氨基酸，其可以并入肽中，其抑制或促进垂体分泌促性腺激素并抑制性腺释放类固醇。 这些非天然氨基酸可用于肽的合成并具有式（a）：其中W为（CH 2）n或 n为1至6的整数; j = 1,2或3，优选Y为N-CN，X为NH，R 2为烷基，改性烷基，烯基，炔基，芳基或甲基吡啶基; 或式（b）：其中R11为H或酰基，W为如（a）中所定义的式（b）：其中R 11为H且W为本文所公开的肽，其为存在十肽GnRH的类似物 在3-，5-，6-和/或8-位的至少一个非天然氨基酸残基。

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。