4-(Pyrrolidinyl)methoxybenzoic acid derivatives as a potent, orally active VLA-4 antagonist |
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| Authors: | Chiba Jun Iimura Shin Yoneda Yoshiyuki Sugimoto Yuichi Horiuchi Takao Muro Fumito Ochiai Yuichi Ogasawara Tomomi Tsubokawa Masao Iigou Yutaka Takayama Gensuke Taira Tomoe Takata Yoshimi Yokoyama Mika Takashi Tohru Nakayama Atsushi Machinaga Nobuo |
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| Institution: | Medicinal Chemistry Research Laboratory, Daiichi Pharmaceutical, Co., Ltd., Tokyo, Japan. chiba2mk@daiichipharm.co.jp |
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| Abstract: | A novel series of benzoic acid derivatives as VLA-4 antagonists were synthesized. Optimization, focusing on activity and lipophilicity needed for cell permeability, resulted in the identification of 15b and 15e with good activity (IC50 = 1.6 nM each) and moderate lipophilicity (Log D = 2.0, 1.8). Furthermore, 15e demonstrated efficacy in murine asthma model by an oral dose of 30 mg/kg. |
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