Improving the Pharmacokinetics of GPR40/FFA1 Full Agonists

Abstract

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