Discovery and Optimization of Potent GPR40 Full Agonists Containing Tricyclic Spirocycles
- ACS Med Chem Lett. 2013 May 7;4(6):551-5. doi: 10.1021/ml300427u.
- 1. Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
GPR40 (FFAR1 or FFA1) is a target of high interest being pursued to treat type II diabetes due to its unique mechanism leading to little risk of hypoglycemia. We recently reported the discovery of AM-1638 (2), a potent full agonist of GPR40. In this report, we present the discovery of GPR40 full agonists containing conformationally constrained tricyclic spirocycles and their structure-activity relationships leading to more potent agonists such as AM-5262 (26) with improved rat PK profile and general selectivity profile. AM-5262 enhanced glucose stimulated Insulin secretion (mouse and human islets) and improved glucose homeostasis in vivo (OGTT in HF/STZ mice) when compared to AM-1638.
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Cat. No.Product NameDescriptionTargetResearch Area
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target: Free Fatty Acid ReceptorResearch Areas: Metabolic Disease