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Discovery of 3-aryl-3-ethoxypropanoic acids as orally active GPR40 agonists
Affiliation:1. Department of Organic and Applied Chemistry, University of Łódź, Tamka 12, 91-403 Łódź, Poland;2. Universite de Lorraine, SRSMC UMR7565, Faculte des Sciences et Techniques, B.P. 70239, F-54506 Vandoeuvre-Les-Nancy Cedex, France;1. Istituto Pasteur Fondazione Cenci Bolognetti, Dipartimento di Scienze di Sanità Pubblica, Sezione di Microbiologia, Sapienza–Università di Roma, P.le A. Moro, 5, 00185 Roma, Italy;2. Istituto Pasteur Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza–Università di Roma, P.le A. Moro, 00185 Roma, Italy;1. Department of Biochemistry and Biotechnology, Laboratory of Bio-Organic Chemistry, University of Thessaly, 26 Ploutonos Str., 41221 Larissa, Greece;2. Department of Chemistry, Aristotle University of Thessaloniki, University Campus, 54124 Thessaloniki, Greece;3. Rega Institute for Medical Research, KU Leuven, B-3000 Leuven, Belgium;1. Division of Cardiology, Duke University Medical Center, Durham, North Carolina;2. Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina;3. Department of Diagnostic and Interventional Radiology (MRI-Core-Lab), Heart Center-University Hospital, Leipzig, Germany;4. CARE Hospital, Hyderabad, India;5. Leeds General Infirmary, Leeds, England;6. Memorial Hermann Heart and Vascular Institute, University of Texas, Houston, Texas;1. Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA;2. Liver Cancer Program, Tisch Cancer Institute, Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA;3. M. & A. Migliavacca Center for Liver Disease and 1st Division of Gastroenterology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy;4. Department of Medicine, Weill Cornell Medical College, Department of Physiology, Biophysics, and Systems Biology, Weill Cornell Medical College, New York, NY, USA
Abstract:The G protein-coupled receptor 40 (GPR40) mediates enhancement of glucose-stimulated insulin secretion in pancreatic β cells. The GPR40 agonist has been attracting attention as a novel insulin secretagogue with glucose dependency for the treatment of type 2 diabetes. The optimization study of compound 1 led to a potent and bioavailable GPR40 agonist 24, which showed insulin secretion and glucose lowering effects in rat OGTT. Compound 24 is a potential lead compound for a novel insulin secretagogue with a low risk of hypoglycemia.
Keywords:GPR40  Agonist  Diabetes  Insulin secretagogue  Glucose lowering
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