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Discovery of novel quinoline carboxylic acid series as DGAT1 inhibitors
Affiliation:1. Department of Chemical Research, Merck Research Laboratories, 126 E. Lincoln Ave., Rahway, NJ 07065, USA;2. Department of Drug Metabolism, Merck Research Laboratories, 126 E. Lincoln Ave., Rahway, NJ 07065, USA;3. Department of Biological Research, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA;1. Discovery Chemistry, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA;2. Discovery Biology, Cardiovascular, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA;3. Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA;1. Department of Discovery Chemistry, Merck Research Laboratories, 2000 Galloping Hill Rd, Kenilworth, NJ 07033, USA;2. Department of Process Chemistry, Merck Research Laboratories, 2000 Galloping Hill Rd, Kenilworth, NJ 07033, USA;3. Department of Chemistry Modeling & Informatics, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA;4. Department of In Vitro Pharmacology, Merck Research Laboratories, 2000 Galloping Hill Rd, Kenilworth, NJ 07033, USA;5. Department of Cardiovascular Diseases, Merck Research Laboratories, 2000 Galloping Hill Rd, Kenilworth, NJ 07033, USA;6. Department of Drug Metabolism, Merck Research Laboratories, 2000 Galloping Hill Rd, Kenilworth, NJ 07033, USA;1. Department of Medicinal Chemistry, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA;2. Department of Metabolic Disorders, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA;3. Department of Pharmacokinetics & Drug Metabolism, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA;1. Toxicology and Ethnoveterinary Medicine, Food, Feed and Veterinary Public Health (FFVPH) Programme, Agricultural Research Council-Onderstepoort Veterinary Institute (ARC-OVI), P/Bag x05, Onderstepoort, 0110, South Africa;2. Department of Paraclinical Sciences, Faculty of Veterinary Science, University of Pretoria, P/Bag x04, Onderstepoort, 0110, South Africa;3. Molecular Epidemiology and Diagnostics (MED) Programme, Agricultural Research Council-Onderstepoort Veterinary Institute (ARC-OVI), P/Bag x05, Onderstepoort, 0110, South Africa;1. Worldwide Medicinal Chemistry, Pfizer Worldwide Research & Development, Cambridge, MA 02139, United States;2. Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development, Cambridge, MA 02139, United States;3. Worldwide Medicinal Chemistry, Pfizer Worldwide Research & Development, Groton, CT 06340, United States;4. Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide Research & Development, Groton, CT 06340, United States
Abstract:Herein we report the design and synthesis of a series of novel bicyclic DGAT1 inhibitors with a carboxylic acid moiety. The optimization of the initial lead compound 7 based on in vitro and in vivo activity led to the discovery of potent indoline and quinoline classes of DGAT1 inhibitors. The structure–activity relationship studies of these novel series of bicyclic carboxylic acid derivatives as DGAT1 inhibitors are described.
Keywords:DGAT1 inhibitor  Triacylglyceride  Diacylglycerol acyltransferase inhibitor  Quinoline  Indoline  Cyclohexanecarboxylic acid
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