Design, synthesis and evaluation of a series of novel phenylpropanoic acid derivatives agonists for the FFA1

This study describes the design, synthesis and biological evaluation of a new series of phenylpropionic acid derivatives as FFA1 agonists with improved potency and moderate physiochemical characteristics. Among them, most promising compounds 7, 14 and 15 were obtained with EC₅₀ values of 82, 79 and 88 nM, exhibited a powerful agonistic activity compared to TAK‐875(95.1 nM). During Oral glucose tolerance test (OGTT) in normal mice, compound 7, 14 and 15 revealed significant glucose‐lowering effect at the dose of 50 mg/kg. Furthermore, compound 15 (50mg/Kg) also exhibited a significant improvement in glucose tolerance in type 2 diabetic mice

Abstract

Free fatty acid 1 (FFA1/GPR40) has attracted extensive attention as a novel target for the treatment of type 2 diabetes for its role in the enhancement of insulin secretion with glucose dependency. Aiming to develop novel potent FFA1 agonists, a new series of phenylpropionic acid derivatives were designed and synthesized on the basis of the modification of chemical cement of TAK‐875, AMG‐837 and LY2881835. Among them, most promising compounds 7, 14 and 15 were obtained with EC₅₀ values of 82, 79 and 88 nM, exhibiting a powerful agonistic activity compared to TAK‐875(95.1 nM). During Oral glucose tolerance test (OGTT) in normal mice, compound 7, 14 and 15 had significant glucose‐lowering effect at the dose of 50 mg/kg. Furthermore, compound 15 (50mg/Kg) also significantly improved in glucose tolerance in type 2 diabetic mice. Herein, we reported the discovery and optimization of a series of potent FFA1 agonists. The discovery supported further exploration surrounding this scaffold.

This article is protected by copyright. All rights reserved.

http://bit.ly/2FCCExz