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Discovery of furan-2-carbohydrazides as orally active glucagon receptor antagonists
Institution:1. Graduate School of Pharmaceutical Sciences, Osaka University, Yamada-oka 1-6, Suita, Osaka 565-0871, Japan;2. Department of Molecular-Targeting Cancer Prevention, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan;1. Medicinal Chemistry, Neuroscience Product Creation Unit, Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire AL10 9SN, UK;2. Pharmacology, Neuroscience Product Creation Unit, Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire AL10 9SN, UK;3. DMPK, Neuroscience Product Creation Unit, Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire AL10 9SN, UK;4. Next Generation Systems Core Function Unit, Eisai Product Creation Systems, Eisai Co., Ltd, 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635 Japan;5. Biomarker and Personalized Medicine Core Function Unit, Eisai Product Creation Systems, Eisai Co., Ltd, 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635 Japan;1. Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, MA 02210, USA;2. Vertex Pharmaceuticals Canada Incorporated, 275 Boul. Armand-Frappier, Laval, QC H7V 4A7, Canada;1. Department of Medicinal Chemistry, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA;2. Department of Pharmaceutics, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA;3. Department of Neuroscience, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA;4. Department of Neuroscience, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA;5. Department of Pharmacokinetics & Drug Metabolism, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA;1. Medicinal Chemistry Department, Boehringer Ingelheim (Canada) Ltd, Research and Development, 2100 Cunard Street, Laval, Quebec H7S 2G5, Canada;2. Biology Department, Boehringer Ingelheim (Canada) Ltd, Research and Development, 2100 Cunard Street, Laval, Quebec H7S 2G5, Canada
Abstract:Furan-2-carbohydrazides were found as orally active glucagon receptor antagonists. Starting from the hit compound 5, we successfully determined the structure activity relationships of a series of derivatives obtained by modifying the acidity of the phenol. We identified the ortho-nitrophenol as a good scaffold for glucagon receptor inhibitory activity. Our efforts have led to the discovery of compound 7l as a potent glucagon receptor antagonist with good bioavailability and satisfactory long half-life.
Keywords:Glucagon  Type 2 diabetes  Furan-2-carbohydrazide  Glucagon receptor antagonist  Hyperglucagonemia
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