2 research outputs found
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