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In vivo pharmacokinetic study and oral glucose tolerance test of sulfoxide analogs of GPR40 agonist TAK ‐875
Author(s) -
Yan Yugang,
Xu Qifu,
Zhao Chunlong,
Dong Hang,
Xu Wenfang,
Zhang Yingjie
Publication year - 2020
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.21675
Subject(s) - sulfoxide , in vivo , sulfone , chemistry , dimethyl sulfoxide , pharmacokinetics , agonist , pharmacology , biological activity , potency , chemical synthesis , stereochemistry , in vitro , biochemistry , organic chemistry , receptor , medicine , biology , microbiology and biotechnology
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.