LY-2881835

TAK‐875 (compound 1) was the only GPR40 agonist with promising oral glucose‐lowering effect, which entered phase III clinical trials. In previous studies, we successfully synthesized the TAK‐875 sulfoxide analog 2, which was further separated to optically pure compounds 3 (S, S, 100.0% de) and 4 (R, S, 100.0% de). In vitro biological evaluation revealed that the sulfoxide analogs 3 and 4 possessed comparable GPR40 agonist activity to TAK‐875. Herein, in order to further evaluate the druglikeness of TAK‐875 sulfoxide analogs, the pharmacokinetic properties of compounds 2, 3, and 4 in rats were investigated and compared with that of TAK‐875. The results showed that sulfoxide (2, 3, and 4) and sulfone (TAK‐875) could be converted into each other in different degrees in vivo. Interestingly, compound 3 showed higher drug exposure calculated by the AUC sum of sulfoxide and sulfone in plasma than TAK‐875, 2 and 4. In order to further investigate the in vivo glucose‐lowering potency of sulfoxide analogs, asymmetric synthesis was carried out and led to two sulfoxides with moderate de values, 5 (S, S, 66.4% de) and 6 (R, S, 71.0% de). The following oral glucose tolerance test (OGTT) in rats showed that 5 (S, S, 66.4% de) had stronger glucose‐lowering effect in vivo than 6 (R, S, 71.0% de) and TAK‐875, which could be partly rationalized by the superior pharmacokinetic property of sulfoxide 3 (the main component of 5) relative to sulfoxide 4 (the main component of 6) and TAK‐875.