Improving the Pharmacokinetics of GPR40/FFA1 Full Agonists

We recently reported the discovery of a potent GPR40 full agonist AM-1638 (<b>1</b>). Herein, we describe our efforts in improving the drug-like properties of the full agonists through the systematic introduction of polar groups in the C-, D-, and A-rings. This led to the discovery of new GPR40 full agonists with significantly improved pharmacokinetic propeties. Compound <b>8</b> and <b>20</b> also showed potent in vivo efficacy in oral glucose tolerance tests in mice in addition to the improvement in properties

Discovery and Optimization of Potent GPR40 Full Agonists Containing Tricyclic Spirocycles

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 (<b>2</b>), 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 (<b>26</b>) 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