13 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 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 glucosestimulated 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 3 (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 40, a compound with low
lipophilicity, excellent in vitro metabolic stability and permeability, complete oral bioavailability, and appreciable efficacy on glucose tolerance in mice