Discovery of HWL-088: A Highly Potent FFA1/GPR40 Agonist Bearing A Phenoxyacetic acid (cas 122-59-8) Scaffold

Add time:09/05/2019    Source:sciencedirect.com

Based on a previously reported Phenoxyacetic acid (cas 122-59-8) scaffold, compound 7 (HWL-088) has been identified as a superior free fatty acid receptor 1 (FFA1) agonist by comprehensive structure-activity relationship study. Our results indicated that the introduction of ortho-fluoro greatly increased the activity of phenoxyacetic acid series, and the unique structure-activity relationship in biphenyl moiety is different from previously reported FFA1 agonists. Moreover, the modeling study was also performed to better understand the binding mode of present series. Compound 7 significantly improved glucose tolerance both in normal and diabetic models, and even exerted greater potential on glucose control than that of TAK-875. These findings provided a novel candidate HWL-088, which is currently in preclinical study to evaluate its potential for the treatment of diabetes.

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