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Discovery of potent and orally bioavailable indazole-based glucagon receptor antagonists for the treatment of type 2 diabetes
Affiliation:1. Discovery Sciences, Janssen Research & Development, L.L.C., Welsh & McKean Roads, Spring House, PA 19477, USA;2. Cardiovascular & Metabolic Research, Janssen Research & Development, L.L.C., Welsh & McKean Roads, Spring House, PA 19477, USA;1. Department of Pathology and Laboratory Medicine, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA;2. Department of Radiation Oncology, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA;3. David Geffen School of Medicine at UCLA, Volunteering Program, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA;4. Jonsson Comprehensive Cancer Center, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA;5. UCLA AIDS Institute, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA;6. Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles, 760 Westwood Plaza, Los Angeles, CA 90024, USA;7. The Pasarow Mass Spectrometry Laboratory, The Jane and Terry Semel Institute for Neuroscience and Human Behavior, 760 Westwood Plaza, Los Angeles, CA 90024, USA;1. School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing 210094, China;2. Shanghai Institute of Organic Chemistry, Chinese Academy of Science, Shanghai 200032, China;1. Department of Discovery Chemistry, Bristol-Myers Squibb, Research and Development, PO Box 5400, Princeton, NJ 08543-5400, United States;2. Department of Cardiovascular Diseases, Bristol-Myers Squibb, Research and Development, PO Box 5400, Princeton, NJ 08543-5400, United States;3. Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Research and Development, PO Box 5400, Princeton, NJ 08543-5400, United States;1. Clinical Laboratory, Beijing Rehabilitation Hospital, Capital Medical University, Beijing 100144, China;2. Gansu Provincial Hospital, Lanzhou, Gansu 730000, China;3. The First Hospital of Lanzhou University, Lanzhou, Gansu, 730000, China
Abstract:Type 2 diabetes mellitus (T2DM) is characterized by chronically elevated plasma glucose levels. The inhibition of glucagon-induced hepatic glucose output via antagonism of the glucagon receptor (GCGR) using a small-molecule antagonist is a promising mechanism for improving glycemic control in the diabetic state. The present work discloses the discovery of indazole-based β-alanine derivatives as potent GCGR antagonists through an efficient enantioselective synthesis and structure-activity relationship (SAR) exploration and optimization. Compounds within this class exhibited excellent pharmacokinetic properties in multiple preclinical species. In an acute dog glucagon challenge test, compound 13K significantly inhibited glucagon-mediated blood glucose increase when dosed orally at 10 mg/kg.
Keywords:Glucagon receptor antagonist  Indazole  Molecular modeling  Diabetes mellitus
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