Discovery of a Potent and Selective Free Fatty Acid Receptor 1 Agonist with Low Lipophilicity and High Oral Bioavailability

The free fatty acid receptor 1 (FFA1, also known as GPR40) mediates enhancement of glucose-stimulated insulin secretion and is emerging as a new target for the treatment of type 2 diabetes. Several FFA1 agonists are known, but the majority of these suffer from high lipophilicity. We have previously reported the FFA1 agonist <b>3</b> (TUG-424). We here describe the continued structure–activity exploration and optimization of this compound series, leading to the discovery of the more potent agonist <b>40</b>, a compound with low lipophilicity, excellent in vitro metabolic stability and permeability, complete oral bioavailability, and appreciable efficacy on glucose tolerance in mice

Discovery of TUG-770: A Highly Potent Free Fatty Acid Receptor 1 (FFA1/GPR40) Agonist for Treatment of Type 2 Diabetes

Free fatty acid receptor 1 (FFA1 or GPR40) enhances glucose-stimulated insulin secretion from pancreatic β-cells and currently attracts high interest as a new target for the treatment of type 2 diabetes. We here report the discovery of a highly potent FFA1 agonist with favorable physicochemical and pharmacokinetic properties. The compound efficiently normalizes glucose tolerance in diet-induced obese mice, an effect that is fully sustained after 29 days of chronic dosing