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CN1443198A - Ghrelin拮抗剂 - Google Patents

Ghrelin拮抗剂 Download PDF

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Publication number
CN1443198A
CN1443198A CN01813240A CN01813240A CN1443198A CN 1443198 A CN1443198 A CN 1443198A CN 01813240 A CN01813240 A CN 01813240A CN 01813240 A CN01813240 A CN 01813240A CN 1443198 A CN1443198 A CN 1443198A
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ser
peptide
pro
leu
phe
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罗马诺·德根吉
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Ardana Bioscience Ltd
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Ardana Bioscience Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/60—Growth hormone-releasing factor [GH-RF], i.e. somatoliberin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/02—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
    • A61P5/04—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin for decreasing, blocking or antagonising the activity of the hypothalamic hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
    • C07K5/1008—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Endocrinology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Toxicology (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Diabetes (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Peptides Or Proteins (AREA)
  • Materials For Photolithography (AREA)
  • Steroid Compounds (AREA)

Abstract

本发明公开了一种新肽，该肽具有对称为Ghrelin的生长激素释放肽的拮抗剂特性。这种新肽可用于降低哺乳动物血循环中的生长激素水平，且具有治疗价值。

Description

Ghrelin拮抗剂
相关申请的交叉参考
本申请要求2000年7月13日提交的临时申请流水号60/220,178的权利。
发明领域
本发明涉及新的生长激素拮抗剂，所述拮抗剂给药于哺乳动物可降低其体内的循环生长激素水平。
发明背景
Ghrelin具有27或28个氨基酸的相关肽的家族名称，所述肽可以在胃中分离得到(M.Kojima et al.，Nature，402，656-660，1999；H.Hosoda et al.，J.Biol.Chem.，May 8,2000)，但产生所述肽的细胞类型在大鼠和人是不同的。所述肽的另外的特征是丝氨酸残基上有一种必要的辛酰酯附着。已知Ghrelin是动物和人体内强效的生长激素(GH)释放物。
通过研究这些肽的合成变异以确定能否对这些肽进行改进，本发明便得自这种研究。
发明概述
我们意外发现具有下述通式的新肽可降低，而不是增加哺乳动物中的循环GH水平：Gly-Ser-Ser(辛酰)-Phe-A(其中A是-OH，NH2，Leu-Ser-Pro-Glu-X或-Ala-Lys-Leu-Gln-Pro-Arg-B，其中B是-OH或NH2)，推测其原因可能是这些肽可拮抗Ghrelin的作用。基于这种原因，这些肽可用来使升高的生长激素水平(如肢端肥大患者或与GH过度产生相关的其它肿瘤患者的升高的生长激素水平)正常化或降低。
发明描述
瞬时肽可通过多种合成方法制备，例如P.LIoyd-Williams等所著的“Chemical Approaches to the Synthesis of Peptides and Proteins(合成肽和蛋白的化学方法)”CRC出版社，New York 1997，和肽化学家熟知的类似方法。
所述肽的水溶液可通过快速输注(bolus injection)或缓慢肠胃外输注以约1-10mg/kg体重的剂量皮下给药。这些肽还可以鼻内或肺内给药，或通过缓释制剂(包括掺入到肽中的可生物降解的多聚体)给药，或通过本领域普通技术人员熟知的其它方法，如可植入的渗透泵等方法给药。
实施例
以下实施例用以说明这些新肽的效果。
实施例1
固相合成以下肽
Gly-Ser-Ser(辛酰)-Phe-Leu-Ser-Pro-Glu
理论MW：948.9，测定值948.9
水中的溶解度为：0.7mg/ml
通过HPLC分析的纯度为：97.8％
以300mg/Kg的剂量给10天龄的大鼠皮下注射所述肽，溶剂对照和Ghrelin，15分钟时检测循环的GH，如R.Deghenghi等，在Life Sciences 54，1321-1328(1994)中所述。结果如下：
    化合物     GH ng/ml
    溶剂对照     10.11±1.6
    Ghrelin(人)     139.80±15.37
    实施例1的肽     1.40±0.32
这表明所述肽拮抗Ghrelin的作用，使GH的释放降低到接近零的水平，远比溶剂对照低。
实施例2
用实施例1的方法制备如下的十四肽：Gly-Ser-Ser(辛酰)-Phe-Leu-Ser-Pro-Glu-Ala-Lys-Leu-Gln-Pro-Arg
理论MW：1642.7 测定MW：1642.7
在水中的溶解度：0.9mg/ml
HPLC分析所得纯度：95.0％
如上述实施例1所述将上述十四肽给药大鼠，所得结果如下：
    化合物     GH ng/ml
    溶剂对照     10.11±1.6
    Ghrelin(人)     140±15
    实施例2的肽     7.00±3.5
本发明的肽再一次表现出拮抗Ghrelin的作用，使GH的释放水平明显低于对照。
实施例3
用实施例1的方法制备如下肽：Gly-Ser-Ser(辛酰)-Phe
理论MW：522.4  测定MW：522.4
在水中的溶解度：不溶
HPLC分析所得纯度：95.6％
如上述实施例1所述给药大鼠这种肽，所得结果如下：
    化合物     GH ng/ml
    溶剂对照     10.1±1.6
    Ghrelin(人)     139.8±15.4
    实施例2的肽     7.7±1.1
本发明的肽再一次表现出拮抗Ghrelin的作用，使GH的释放水平明显低于对照。
                      序列表
                      序列表<110>阿达纳生物科学有限公司(Ardana Bioscience Limited)<120>GHRELIN拮抗剂<130>ARDW/P26793PC<140>PCT/EP01/07929<141>2001-07-10<150>US 60/220,178<151>2000-07-13<160>4<170>PatentIn version 3.1<210>1<211>5<212>PRT<213>人工序列<220><223>一种人工序列，其是已知Ghrelin肽的合成变异，这种Ghrelin肽分离自大鼠和人类胃中的不同细胞类型.<220><221>MOD_RES<222>(3)..(3)<223>辛酰酯附着到丝氨酸残基<220><221>MISC_FEATURE<222>(5)..(5)<223>X是OH，NH2，Leu-Ser-Pro-Glu-X，或Ala-Lys-Leu-Gln-Pro-Arg-B，B是OH orNH2.<400>1Gly Ser Ser Phe Xaa1               5<210>2<211>8<212>PRT<213>人工序列<220><223>一种人工序列，其是已知Ghrelin肽的合成变异，这种Ghrelin肽分离自大鼠和人类胃中的不同细胞类型.<220><221>MOD_RES<222>(3)..(3)<223>辛酰酯附着到丝氨酸残基<400>2Gly Ser Ser Phe Leu Ser Pro Glu1               5<210>3<211>14<212>PRT<213>人工序列<220><223>一种人工序列，其是已知Ghrelin肽的合成变异，这种Ghrelin肽分离自大鼠和人类胃中的不同细胞类型。<220><221>MOD_RES<222>(3)..(3)<223>辛酰酯附着到丝氨酸残基<400>3Gly Ser Ser Phe Leu Set Pro Glu Ala Lys Leu Gln Pro Arg1               5                   10<210>4<211>4<212>PRT<213>人工序列<220><223>一种人工序列，其是已知Ghrelin肽的合成变异，这种Ghrelin肽分离大鼠和人类胃中的不同细胞类型。<220><221>MOD_RES<222>(3)..(3)<223>辛酰酯附着到丝氨酸残基<400>4Gly Ser Ser Phe1

Claims (18)

1.一种具有如下通式的Ghrelin拮抗剂肽，
Gly-Ser-Ser(辛酰)-Phe-A，其中A是-OH，NH2，Leu-Ser-Pro-Glu-B，或-Ala-Lys-Leu-Gln-Pro-Arg-B，其中B是-OH或NH2，其中所述肽给药哺乳动物后具有拮抗Ghrelin的作用。
2.权利要求1的肽，具体指Gly-Ser-Ser(辛酰)-Phe-Leu-Ser-Pro-Glu。
3.权利要求1的肽，具体指Gly-Ser-Ser(辛酰)-Phe-Leu-Ser-Pro-Glu-Ala-Lys-Leu-Gln-Pro-Arg。
4.权利要求1的肽，具体指Gly-Ser-Ser(辛酰)-Phe。
5.包含权利要求1的肽的药物组合物，其形式是可药用盐。
6.权利要求5的组合物，其进一步包含载体。
7.权利要求5的组合物，其形式是缓释制剂或用于肠胃外给药的装置。
8.权利要求5的肽，其形式是可鼻内用药的制剂。
9.权利要求5的肽，其形式是可吸入用药的制剂。
10.一种使哺乳动物中升高的生长激素水平正常化的方法，该方法是向需要此种治疗的哺乳动物给药有效剂量的至少一种权利要求1的肽。
11.权利要求10的方法，其中所述肽是Gly-Ser-Ser(辛酰)-Phe-Leu-Ser-Pro-Glu。
12.权利要求11的方法，其中所述肽是Gly-Ser-Ser(辛酰)-Phe-Leu-Ser-Pro-Glu-Ala-Lys-Leu-Gln-Pro-Arg。
13.权利要求12的方法，其中所述肽是Gly-Ser-Ser(辛酰)-Phe。
14.权利要求10的方法，其中所述肽作为缓释制剂给药，或借助用于肠胃外给药的装置来给药。
15.权利要求10的方法，其中所述肽作为可鼻内用药的制剂给药。
16.权利要求10的方法，其中所述肽以可吸入用药的制剂给药。
17.权利要求10的方法，其中所述肽以每公斤哺乳动物体重约1-10毫克的剂量给药。
18.权利要求10的方法，其中所述肽给予肢端肥大的哺乳动物。
CN01813240A 2000-07-24 2001-07-10 Ghrelin拮抗剂 Pending CN1443198A (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US22017800P 2000-07-24 2000-07-24
US60/220,178 2000-07-24

Publications (1)

Publication Number Publication Date
CN1443198A true CN1443198A (zh) 2003-09-17

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US (1) US20020187938A1 (zh)
EP (1) EP1303538A2 (zh)
JP (1) JP2004504406A (zh)
KR (1) KR20030033002A (zh)
CN (1) CN1443198A (zh)
AU (1) AU2001283938A1 (zh)
CA (1) CA2416643A1 (zh)
MX (1) MXPA03000738A (zh)
WO (1) WO2002008250A2 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1637416B (zh) * 2003-10-16 2011-08-17 霍夫曼-拉罗奇有限公司 标记的生长素促分泌素及其合成方法和用途

Families Citing this family (74)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002090387A1 (en) * 2001-05-10 2002-11-14 Queensland University Of Technology Reproductive cancer diagnosis and therapy
US7105526B2 (en) 2002-06-28 2006-09-12 Banyu Pharmaceuticals Co., Ltd. Benzimidazole derivatives
CN1665565A (zh) * 2002-07-19 2005-09-07 赛托斯生物技术公司 Ghrelin－载体偶联物
WO2004009616A2 (en) * 2002-07-23 2004-01-29 Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) Ghrelin analogs
TWI331922B (en) 2002-08-09 2010-10-21 Ipsen Pharma Sas Growth hormone releasing peptides
US20040121407A1 (en) * 2002-09-06 2004-06-24 Elixir Pharmaceuticals, Inc. Regulation of the growth hormone/IGF-1 axis
US7772188B2 (en) 2003-01-28 2010-08-10 Ironwood Pharmaceuticals, Inc. Methods and compositions for the treatment of gastrointestinal disorders
WO2005012332A1 (en) * 2003-07-31 2005-02-10 Tranzyme Pharma Spatially-defined macrocycles incorporating peptide bond surrogates
AU2004261329B2 (en) 2003-07-31 2011-10-27 Ocera Therapeutics, Inc. Spatially-defined macrocyclic compounds useful for drug discovery
EP1663289A2 (en) * 2003-08-29 2006-06-07 Amylin Pharmaceuticals, Inc. Methods for treating or ameliorating ghrelin-associated diseases and disorders
AU2004274309B2 (en) 2003-09-22 2010-04-08 Msd K.K. Novel piperidine derivative
EP1734963A4 (en) 2004-04-02 2008-06-18 Merck & Co Inc METHOD FOR TREATING PEOPLE WITH METABOLIC AND ANTHROPOMETRIC DISORDER
JP2007537434A (ja) * 2004-05-14 2007-12-20 ノボ　ノルディスク　アクティーゼルスカブ 機能的ｇｈｓ−ｒアンタゴニスト
CA2584806C (en) 2004-11-01 2014-06-17 Amylin Pharmaceuticals, Inc. Treatment of obesity and related disorders
US7187208B2 (en) * 2005-01-19 2007-03-06 Phaselink Semiconductor Corporation Complimentary metal oxide silicon low voltage positive emitter coupled logic buffer
WO2007022123A2 (en) 2005-08-11 2007-02-22 Amylin Pharmaceuticals, Inc. Hybrid polypeptides with selectable properties
US7737155B2 (en) 2005-05-17 2010-06-15 Schering Corporation Nitrogen-containing heterocyclic compounds and methods of use thereof
CA2609388C (en) 2005-05-30 2013-08-06 Banyu Pharmaceutical Co., Ltd. Novel piperidine derivative
US20090275648A1 (en) * 2005-06-13 2009-11-05 Fraser Graeme L Macrocyclic ghrelin receptor antagonists and inverse agonists and methods of using the same
WO2007018248A1 (ja) 2005-08-10 2007-02-15 Banyu Pharmaceutical Co., Ltd. ピリドン化合物
BRPI0614649A2 (pt) 2005-08-11 2011-04-12 Amylin Pharmaceuticals Inc polipeptìdeos hìbridos com propriedades selecionáveis
EP1921065B1 (en) 2005-08-24 2010-10-20 Banyu Pharmaceutical Co., Ltd. Phenylpyridone derivative
CA2621470A1 (en) 2005-09-07 2007-03-15 Banyu Pharmaceutical Co., Ltd. Bicyclic aromatic substituted pyridone derivative
RU2427587C2 (ru) * 2005-09-28 2011-08-27 Ипсен Фарма С.А.С. Аналоги грелина
WO2007038678A2 (en) 2005-09-28 2007-04-05 Societe De Conseils De Recherches Et D'applications Scientifiques S.A.S. Analogs of ghrelin
EP1937262B1 (en) 2005-09-29 2019-05-08 Ipsen Pharma Composition for use in treating gastrointestinal dysmotility
KR20080048502A (ko) 2005-09-29 2008-06-02 머크 앤드 캄파니 인코포레이티드 멜라노코르틴-4 수용체 조절제로서의 아실화스피로피페리딘 유도체
AU2006307046A1 (en) 2005-10-27 2007-05-03 Msd K.K. Novel benzoxathiin derivative
US8158791B2 (en) 2005-11-10 2012-04-17 Msd K.K. Aza-substituted spiro derivatives
WO2007092023A1 (en) 2006-02-11 2007-08-16 Boston Biomedical Research Institute Compositions and methods for binding or inactivating ghrelin
US8088733B2 (en) 2006-07-06 2012-01-03 Tranzyme Pharma Inc. Methods of using macrocyclic agonists of the ghrelin receptor for treatment of gastrointestinal motility disorders
JP5489333B2 (ja) 2006-09-22 2014-05-14 メルク・シャープ・アンド・ドーム・コーポレーション 脂肪酸合成阻害剤を用いた治療の方法
WO2008047544A1 (en) 2006-09-28 2008-04-24 Banyu Pharmaceutical Co., Ltd. Diaryl ketimine derivative
AU2008233662B2 (en) 2007-04-02 2012-08-23 Msd K.K. Indoledione derivative
CA2686616A1 (en) * 2007-05-14 2009-02-12 Suzanne L. Dickson New treatment for chemical substance addiction
US8969514B2 (en) 2007-06-04 2015-03-03 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases
US7879802B2 (en) 2007-06-04 2011-02-01 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
EP2264026A4 (en) 2008-03-06 2012-03-28 Msd Kk ALKYLAMINOPYRIDINDERIVATE
EP2272841A1 (en) 2008-03-28 2011-01-12 Banyu Pharmaceutical Co., Ltd. Diarylmethylamide derivative having antagonistic activity on melanin-concentrating hormone receptor
AU2009256157B2 (en) 2008-06-04 2014-12-18 Bausch Health Ireland Limited Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
JPWO2009154132A1 (ja) 2008-06-19 2011-12-01 Ｍｓｄ株式会社 スピロジアミン−ジアリールケトオキシム誘導体
JP2011528375A (ja) 2008-07-16 2011-11-17 シナジー ファーマシューティカルズ インコーポレイテッド 胃腸障害、炎症、癌、およびその他の障害の治療のために有用なグアニル酸シクラーゼのアゴニスト
EP2319841A1 (en) 2008-07-30 2011-05-11 Msd K.K. (5-membered)-(5-membered) or (5-membered)-(6-membered) fused ring cycloalkylamine derivative
MX2011004258A (es) 2008-10-22 2011-06-01 Merck Sharp & Dohme Derivados de bencimidazol ciclicos novedosos utiles como agentes anti-diabeticos.
JP5635991B2 (ja) 2008-10-30 2014-12-03 メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． イソニコチンアミドオレキシン受容体アンタゴニスト
WO2010051206A1 (en) 2008-10-31 2010-05-06 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents
US20110245209A1 (en) 2008-12-16 2011-10-06 Schering Corporation Pyridopyrimidine derivatives and methods of use thereof
EP2379562A1 (en) 2008-12-16 2011-10-26 Schering Corporation Bicyclic pyranone derivatives as nicotinic acid receptor agonists
EP2493910A1 (en) 2009-10-30 2012-09-05 Tranzyme Pharma, Inc. Macrocyclic ghrelin receptor antagonists and inverse agonists and methods of using the same
WO2011106273A1 (en) 2010-02-25 2011-09-01 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents
US9616097B2 (en) 2010-09-15 2017-04-11 Synergy Pharmaceuticals, Inc. Formulations of guanylate cyclase C agonists and methods of use
WO2012116145A1 (en) 2011-02-25 2012-08-30 Merck Sharp & Dohme Corp. Novel cyclic azabenzimidazole derivatives useful as anti-diabetic agents
AR088352A1 (es) 2011-10-19 2014-05-28 Merck Sharp & Dohme Antagonistas del receptor de 2-piridiloxi-4-nitrilo orexina
WO2013119800A1 (en) 2012-02-07 2013-08-15 Massachusetts Institute Of Technology Use of antagonists of ghrelin or ghrelin receptor to prevent or treat stress-sensitive psychiatric illness
WO2014022528A1 (en) 2012-08-02 2014-02-06 Merck Sharp & Dohme Corp. Antidiabetic tricyclic compounds
CA2898482A1 (en) 2013-02-22 2014-08-28 Linda L. Brockunier Antidiabetic bicyclic compounds
EP2970119B1 (en) 2013-03-14 2021-11-03 Merck Sharp & Dohme Corp. Novel indole derivatives useful as anti-diabetic agents
US9724396B2 (en) 2013-03-15 2017-08-08 Massachusetts Institute Of Technology Use of antagonists of growth hormone or growth hormone receptor to prevent or treat stress-sensitive psychiatric illness
JP2016514671A (ja) 2013-03-15 2016-05-23 シナジー ファーマシューティカルズ インコーポレイテッド グアニル酸シクラーゼのアゴニストおよびその使用
AU2014235209B2 (en) 2013-03-15 2018-06-14 Bausch Health Ireland Limited Guanylate cyclase receptor agonists combined with other drugs
AU2014274812B2 (en) 2013-06-05 2018-09-27 Bausch Health Ireland Limited Ultra-pure agonists of guanylate cyclase C, method of making and using same
WO2015051496A1 (en) 2013-10-08 2015-04-16 Merck Sharp & Dohme Corp. Antidiabetic tricyclic compounds
US20160235807A1 (en) 2013-10-09 2016-08-18 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for downregulation of pro-inflammatory cytokines
US9119832B2 (en) 2014-02-05 2015-09-01 The Regents Of The University Of California Methods of treating mild brain injury
US9708272B2 (en) 2014-08-29 2017-07-18 Tes Pharma S.R.L. Inhibitors of α-amino-β-carboxymuconic acid semialdehyde decarboxylase
WO2016138099A1 (en) 2015-02-24 2016-09-01 Massachusetts Institute Of Technology Use of ghrelin or functional ghrelin receptor agonists to prevent and treat stress-sensitive psychiatric illness
EP3526199B1 (en) 2016-10-14 2022-04-13 Tes Pharma S.r.l. Inhibitors of alpha-amino-beta-carboxymuconic acid semialdehyde decarboxylase
WO2018106518A1 (en) 2016-12-06 2018-06-14 Merck Sharp & Dohme Corp. Antidiabetic heterocyclic compounds
WO2018118670A1 (en) 2016-12-20 2018-06-28 Merck Sharp & Dohme Corp. Antidiabetic spirochroman compounds
MX2021005904A (es) 2018-11-20 2021-09-08 Tes Pharma S R L Inhibidores de la ácido alfa-amino-beta-carboximucónico semialdehído descarboxilasa.
US12331018B2 (en) 2019-02-13 2025-06-17 Merck Sharp & Dohme Llc Pyrrolidine orexin receptor agonists
EP3924058B1 (en) 2019-02-13 2026-01-07 Merck Sharp & Dohme LLC 5-alkyl pyrrolidine orexin receptor agonists
US12312332B2 (en) 2019-08-08 2025-05-27 Merck Sharp & Dohme Llc Heteroaryl pyrrolidine and piperidine orexin receptor agonists
EP4200295A1 (en) 2020-08-18 2023-06-28 Merck Sharp & Dohme LLC Bicycloheptane pyrrolidine orexin receptor agonists

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL147652A0 (en) * 1999-07-23 2002-08-14 Kangawa Kenji Novel peptides
CA2411667A1 (en) * 2000-05-30 2001-12-06 Merck & Co. Inc. Ghrelin analogs

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1637416B (zh) * 2003-10-16 2011-08-17 霍夫曼-拉罗奇有限公司 标记的生长素促分泌素及其合成方法和用途

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