Synthesis and biological evaluation of benzoic acid derivatives as potent, orally active VLA-4 antagonists

…, Y Yoneda, T Watanabe, F Muro, M Tsubokawa…

Index: Chiba, Jun; Iimura, Shin; Yoneda, Yoshiyuki; Watanabe, Toshiyuki; Muro, Fumito; Tsubokawa, Masao; Iigou, Yutaka; Satoh, Atsushi; Takayama, Gensuke; Yokoyama, Mika; Takashi, Tohru; Nakayama, Atsushi; Machinaga, Nobuo Bioorganic and Medicinal Chemistry, 2007 , vol. 15, # 4 p. 1679 - 1693

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Citation Number: 14

Abstract

A series of benzoic acid derivatives was synthesized as VLA-4 antagonists. Introduction of chlorine or bromine into the 3-position on the central benzene of the diphenylurea portion as in lead compound 2 led to improvement in the pharmacokinetic properties. In particular, 12l demonstrated an acceptable plasma clearance and bioavailability in mice and rats as well as dogs (mice, CL= 18.5 ml/min/kg, F= 28%; rats, CL= 5.2 ml/min/kg, F= 36%; dogs, CL= ...