2. Academic Validation
  3. Discovery of trans-4-[1-[[2,5-Dichloro-4-(1-methyl-3-indolylcarboxamido)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid: an orally active, selective very late antigen-4 antagonist

Discovery of trans-4-[1-[[2,5-Dichloro-4-(1-methyl-3-indolylcarboxamido)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid: an orally active, selective very late antigen-4 antagonist

  • J Med Chem. 2009 Dec 24;52(24):7974-92. doi: 10.1021/jm901154c.
Fumihito Muro 1,  Shin Iimura,  Yuuichi Sugimoto,  Yoshiyuki Yoneda,  Jun Chiba,  Toshiyuki Watanabe,  Masaki Setoguchi,  Yutaka Iigou,  Keiko Matsumoto,  Atsushi Satoh,  Gensuke Takayama,  Tomoe Taira,  Mika Yokoyama,  Tohru Takashi,  Atsushi Nakayama,  Nobuo Machinaga
Affiliations

Affiliation

  • 1 R&D Division, Daiichi Sankyo Co., Ltd., Tokyo 134-8630, Japan. muro.fumihito.iy@daiichisankyo.co.jp
PMID: 19891440 DOI: 10.1021/jm901154c
Abstract

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 (IC(50) = 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.

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