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.

Free Fatty Acid Receptor 1 (FFAR1) as an Emerging Therapeutic Target for Type 2 Diabetes Mellitus: Recent Progress and Prevailing Challenges.

Discovery of first-in-class thiazole-based dual FFA1/PPARδ agonists as potential anti-diabetic agents.

Design, synthesis, and biological evaluation of novel pan agonists of FFA1, PPARγ and PPARδ.

Discovery of phenylsulfonyl acetic acid derivatives with improved efficacy and safety as potent free fatty acid receptor 1 agonists for the treatment of type 2 diabetes.

Design, synthesis and structure-activity relationship studies of novel free fatty acid receptor 1 agonists bearing amide linker.

The free fatty acid receptor 1 (FFA1) plays a key role in amplifying glucose-stimulated insulin secretion in pancreatic β-cells. Most of the reported FFA1 agonists contain a biphenyl scaffold, which is associated with toxicity as verified by Daiichi Sankyo. Herein, we describe the systematic exploration of a non-biphenyl scaffold to improve the druggability of GW9508 (β-oxidation, Fsp3 = 0.13, tPSA = 58.5 A2) directed by Fsp3 and tPSA values. All these optimizations ultimately led to the identification of compound 21, an unconventional agonist (EC50 = 72.5 nM) bearing a methyl oxime ether scaffold. Moreover, compound 21 revealed improved drug-like properties (Fsp3 = 0.23, tPSA = 86.6 A2) when compared to GW9508 (Fsp3 = 0.13, tPSA = 58.5 A2) and an even higher binding efficiency index (BEI = 15.3) than TAK-875 (BEI = 14.3). Further pharmacological studies suggested that compound 21 has a considerable hypoglycemic effect in both normal and type 2 diabetic mice with a low risk of hypoglycemia. In addition, the docking study promoted our understanding of the ligand-binding pocket. This information might help towards the design of more promising new molecular entities.

Discovery of a novel oxime ether scaffold as potent and orally bioavailable free fatty acid receptor 1 agonists

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Discovery of a novel oxime ether scaffold as potent and orally bioavailable free fatty acid receptor 1 agonists