Identification of 4-[1-[3-chloro-4-[N’-(5-fluoro-2-methylphenyl)ureido]phenylacetyl]-(4S)-fluoro-(2S)-pyrrolidinylmethoxy]benzoic acid as a potent, orally active VLA-4 antagonist

Optimization of benzoic acid derivatives by introducing substituents into the diphenyl urea moiety led to the identification of compound 20l as a potent VLA-4 antagonist. Compound 20l inhibited eosinophil infiltration into bronchial alveolar lavage fluid in a murine asthma model by oral dosing and its efficacy was comparable to anti-mouse α4 antibody (R1-2). Furthermore, this compound significantly blocked bronchial hyper-responsiveness in the model.

A series of benzoic acid derivatives were synthesized and evaluated for VLA-4 inhibitory activity in a receptor binding assay. A representative compound 20l demonstrated efficacy in murine asthma model by oral dosing.Figure optionsDownload as PowerPoint slide