Identification of a novel conformationally constrained glucagon receptor antagonist |
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| Institution: | 1. Pfizer Worldwide Research & Development, 620 Memorial Drive, Cambridge, MA 02139, United States;2. Pfizer Worldwide Research & Development, Eastern Point Rd., Groton, CT 06340, United States;1. Cambridge Laboratories, Pfizer Worldwide Research & Development, 620 Memorial Drive, Cambridge, MA 02139, United States;2. Groton Laboratories, Pfizer Worldwide Research & Development, Eastern Point Road, Groton, CT 06340, United States;1. Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Rd, La Jolla, CA 92037, United States;2. Department of Chemical Physiology, The Scripps Research Institute, 10550 N. Torrey Pines Rd, La Jolla, CA 92037, United States;3. The Scripps Research Institute Molecular Screening Center, 10550 N. Torrey Pines Rd, La Jolla, CA 92037, United States;4. Department of Immunology, The Scripps Research Institute, 10550 N. Torrey Pines Rd, La Jolla, CA 92037, United States;1. Boehringer Ingelheim Pharma GmbH & Co. KG, Department of Medicinal Chemistry, Birkendorfer Str. 65, 88397 Biberach an der Riss, Germany;2. Boehringer Ingelheim Pharma GmbH & Co. KG, Department of Cardiometabolic Research, Birkendorfer Str. 65, 88397 Biberach an der Riss, Germany;3. Boehringer Ingelheim Pharma GmbH & Co. KG, Department of Drug Discovery Support Research Germany, Birkendorfer Str. 65, 88397 Biberach an der Riss, Germany;1. Lead Identification and Optimization Support, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, D-88397 Biberach a.d. Riss, Germany;2. Medicinal Chemistry, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, D-88397 Biberach a.d. Riss, Germany;3. Drug Discovery Support, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, D-88397 Biberach a.d. Riss, Germany;4. Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, D-88397 Biberach a.d. Riss, Germany;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 |
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| Abstract: | Identification of orally active, small molecule antagonists of the glucagon receptor represents a novel treatment paradigm for the management of type 2 diabetes mellitus. The present work discloses novel glucagon receptor antagonists, identified via conformational constraint of current existing literature antagonists. Optimization of lipophilic ligand efficiency (LLE or LipE) culminated in enantiomers (+)-trans-26 and (−)-trans-27 which exhibit good physicochemical and in vitro drug metabolism profiles. In vivo, significant pharmacokinetic differences were noted with the two enantiomers, which were primarily driven through differences in clearance rates. Enantioselective oxidation by cytochrome P450 was ruled out as a causative factor for pharmacokinetic differences. |
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| Keywords: | Glucagon receptor antagonist Diabetes mellitus Physicochemical properties Metabolite |
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