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