Bioorganic & Medicinal Chemistry 2008-12-01

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.

Fumihito Muro, Shin Iimura, Yoshiyuki Yoneda, Jun Chiba, Toshiyuki Watanabe, Masaki Setoguchi, Yutaka Iigou, Gensuke Takayama, Mika Yokoyama, Tohru Takashi, Atsushi Nakayama, Nobuo Machinaga

Index: Bioorg. Med. Chem. 16(23) , 9991-10000, (2008)

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Abstract

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 alpha4 antibody (R1-2). Furthermore, this compound significantly blocked bronchial hyper-responsiveness in the model.