1 research outputs found
Discovery and Optimization of an Azetidine Chemical Series As a Free Fatty Acid Receptor 2 (FFA2) Antagonist: From Hit to Clinic
FFA2,
also called GPR43, is a G-protein coupled receptor for short chain
fatty acids which is involved in the mediation of inflammatory responses.
A class of azetidines was developed as potent FFA2 antagonists. Multiparametric
optimization of early hits with moderate potency and suboptimal ADME
properties led to the identification of several compounds with nanomolar
potency on the receptor combined with excellent pharmacokinetic (PK)
parameters. The most advanced compound, 4-[[(<i>R</i>)-1-(benzo[<i>b</i>]thiophene-3-carbonyl)-2-methyl-azetidine-2-carbonyl]-(3-chloro-benzyl)-amino]-butyric
acid <b>99</b> (GLPG0974), is able to inhibit acetate-induced
neutrophil migration strongly in vitro and demonstrated ability to
inhibit a neutrophil-based pharmacodynamic (PD) marker, CD11b activation-specific
epitope [AE], in a human whole blood assay. All together, these data
supported the progression of <b>99</b> toward next phases, becoming
the first FFA2 antagonist to reach the clinic