Discovery of trans-4-[1-[[2,5-Dichloro-4-(1-methyl-3-indolylcarboxamido)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic Acid: An Orally Active, Selectiv

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• 作者：Fumihito Muro ; Shin Iimura ; Yuuichi Sugimoto ; Yoshiyuki Yoneda ; Jun Chiba ; Toshiyuki Watanabe ; Masaki Setoguchi ; Yutaka Iigou ; Keiko Matsumoto ; Atsushi Satoh ; Gensuke Takayama ; Tomoe Taira ; Mika Yokoy
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：December 24, 2009
• 年：2009
• 卷：52
• 期：24
• 页码：7974-7992
• 全文大小：1191K
• 年卷期：v.52,no.24(December 24, 2009)
• ISSN：1520-4804

文摘

We have focused on optimization of the inadequate pharmacokinetic profile of trans-4-substituted cyclohexanecarboxylic acid 5, which is commonly observed in many small molecule very late antigen-4 (VLA-4) antagonists. We modified the lipophilic moiety in 5 and found that reducing the polar surface area of this moiety results in improvement of the PK profile. Consequently, our efforts have led to the discovery of trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxamido)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid (14e) with potent activity (IC₅₀ = 5.4 nM) and significantly improved bioavailability in rats, dogs, and monkeys (100%, 91%, 68%), which demonstrated excellent oral efficacy in murine and guinea pig models of asthma. Based on its overall profile, compound 14e was progressed into clinical trails. In a single ascending-dose phase I clinical study, compound 14e exhibited favorable oral exposure as expected and had no serious adverse events.