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A novel and potent VLA-4 antagonist based on trans-4-substituted cyclohexanecarboxylic acid.

Bioorganic & medicinal chemistry (2009-01-07)
Fumihito Muro, Shin Iimura, Yoshiyuki Yoneda, Jun Chiba, Toshiyuki Watanabe, Masaki Setoguchi, Gensuke Takayama, Mika Yokoyama, Tohru Takashi, Atsushi Nakayama, Nobuo Machinaga
ZUSAMMENFASSUNG

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.

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Cyclohexancarbonsäure, 98%
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