Journal
MEDICINAL RESEARCH REVIEWS
Volume 38, Issue 2, Pages 381-425Publisher
WILEY
DOI: 10.1002/med.21441
Keywords
free fatty acid; GPR40; GLP-1; type 2 diabetes; toxicity
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Funding
- National Natural Science Foundation of China [81673299, 81273376, 81172932]
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The free fatty acid receptor 1 (FFAR1/GPR40) amplifies glucose-dependent insulin secretion; therefore, it has attracted widespread attention as a promising antidiabetic target. Current clinical proof of concept also indicates that FFAR1 agonists achieve the initially therapeutic endpoint for the treatment of type 2 diabetes mellitus (T2DM) without the hypoglycemic risk. Thus, many pharmaceutical companies and academic institutes are competing to develop FFAR1 agonists. However, several candidates have been discontinued in clinical trials, often without reporting the underlying reasons. Herein, we review the challenges and corresponding strategies chosen by different medicinal chemistry teams to improve the physicochemical properties, potency, pharmacokinetics, and safety profiles of FFAR1 agonists, with a brief introduction to the biology and pharmacology of related targets. (C) 2017 Wiley Periodicals, Inc.
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