期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 5, 期 5, 页码 517-521出版社
AMER CHEMICAL SOC
DOI: 10.1021/ml400501x
关键词
GPR40; FFAR1; FFA1; GPCR; agonist; type II diabetes; insulin secretagogue
GPR40 (FFA1 and FFAR1) has gained significant interest as a target for the treatment of type 2 diabetes. TAK-875 (1), a GPR40 agonist, lowered hemoglobin A1c (HbA1c) and lowered both postprandial and fasting blood glucose levels in type 2 diabetic patients in phase II clinical trials. We optimized phenylpropanoic acid derivatives as GPR40 agonists and identified AMG 837 (2) as a clinical candidate. Here we report our efforts in searching for structurally distinct back-ups for AMG 837. These efforts led to the identification of more polar GPR40 agonists, such as AM-4668 (10), that have improved potency, excellent pharmacokinetic properties across species, and minimum central nervous system (CNS) penetration.
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