A novel and potent VLA-4 antagonist based on trans-4-substituted cyclohexanecarboxylic acid |
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| Authors: | Fumihito Muro Shin Iimura Yoshiyuki Yoneda Jun Chiba Toshiyuki Watanabe Masaki Setoguchi Gensuke Takayama Mika Yokoyama Tohru Takashi Atsushi Nakayama Nobuo Machinaga |
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| Affiliation: | 1. Medicinal Chemistry Research Laboratories II, Daiichi Sankyo Co., Ltd, 1-16-13, Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan;2. Medicinal Chemistry Research Laboratories I, Daiichi Sankyo Co., Ltd, 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan;3. Biological Research Laboratories III, Daiichi Sankyo, Co., Ltd, 1-16-13, Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan;4. Biological Research Laboratories IV, Daiichi Sankyo, Co., Ltd, 1-16-13, Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan |
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| 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, IC50 = 19 nM) in VLA-4 inhibitory activity compared to 1 (IC50 = 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 (IC50 = 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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