FFA2,also called GPR43, is a G-protein coupled receptor for short chainfatty acids which is involved in the mediation of inflammatory responses.A class of azetidines was developed as potent FFA2 antagonists. Multiparametricoptimization of early hits with moderate potency and suboptimal ADMEproperties led to the identification of several compounds with nanomolarpotency on the receptor combined with excellent pharmacokinetic (PK)parameters. The most advanced compound, 4-[[(R)-1-(benzo[b]thiophene-3-carbonyl)-2-methyl-azetidine-2-carbonyl]-(3-chloro-benzyl)-amino]-butyricacid 99(GLPG0974), is able to inhibit acetate-inducedneutrophil migration strongly in vitro and demonstrated ability toinhibit a neutrophil-based pharmacodynamic (PD) marker, CD11b activation-specificepitope [AE], in a human whole blood assay. All together, these datasupported the progression of 99toward next phases, becomingthe first FFA2 antagonist to reach the clinic. [ABSTRACT FROM AUTHOR]