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

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

Medicinal Chemistry Research Laboratories II, Daiichi Sankyo Co., Ltd, 1-16-13, Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan. muro.fumihito.iy@daiichisankyo.co.jp

Bioorganic & medicinal chemistry 2009 Feb 1

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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.

Citation

Fumihito Muro, Shin Iimura, Yoshiyuki Yoneda, Jun Chiba, Toshiyuki Watanabe, Masaki Setoguchi, Gensuke Takayama, Mika Yokoyama, Tohru Takashi, Atsushi Nakayama, Nobuo Machinaga. A novel and potent VLA-4 antagonist based on trans-4-substituted cyclohexanecarboxylic acid. Bioorganic & medicinal chemistry. 2009 Feb 1;17(3):1232-43