GPR40 (FFAR1 or FFA1) is a target of high interest being pursued to treat type II diabetes due to its unique mechanism pointing to little risk of hypoglycemia. We recently reported the discovery of AM-1638 (2  ), a potent full agonist of GPR40. Here in, we present the discovery of full agonists containing conformationally constrained tricyclic spirocycles and their structure�activity relationships leading to more potent GPR40 full agonists such as AM-5262 (19 ) with improved PK and selectivity profiles.Our efforts defining conformational constraints started by constraining the flexible phenylpropanoic acid region with a 5-membered ring, followed by exploring different connections of a cyclopropane to the 5-membered ring. We then further looked at different ring sizes of the tricyclic spirocycles and many of these modifications resulted in potent GPR40 full agonists.AM-5262 binds to the same ligand site on GPR40 as AM-1638, 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.

Discovery and optimization of potent GPR40 full agonists containing tricyclic spirocycles

245th National Meeting (2013)

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