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ID: ALA1143341
Journal: Bioorg Med Chem
Title: A novel and potent VLA-4 antagonist based on trans-4-substituted cyclohexanecarboxylic acid.
Authors: Muro F, Iimura S, Yoneda Y, Chiba J, Watanabe T, Setoguchi M, Takayama G, Yokoyama M, Takashi T, Nakayama A, Machinaga N.
Abstract: During the course of our study, it was revealed that the poor pharmacokinetic properties of a series of benzoic acid derivatives such as 1 should be attributed to the diphenylurea moiety. Thus, we replaced the diphenylurea moiety in 1 with a 2-(2-methylphenylamino)benzoxazole moiety which mimics the diphenylurea structure. However, this modification resulted in a significant decrease (3, IC(50)=19 nM) in VLA-4 inhibitory activity compared to 1 (IC(50)=1.6 nM). To address this discrepancy, we worked on optimization of the carboxylic acid moiety in compound 3. As a result, our efforts have led to the discovery of trans-4-substituted cyclohexanecarboxylic acid derivative 11b (IC(50)=2.8 nM) as a novel and potent VLA-4 antagonist. In addition, compound 11b exhibited favorable pharmacokinetic properties (CL=3.3 ml/min/kg, F=51%) in rats.
CiteXplore: 19124247