4-(Pyrrolidinyl)methoxybenzoic Acid Derivatives as a Potent, Orally Active VLA-4 Antagonist

    • CHIBA Jun
    • Medicinal Chemistry Research Laboratory, Daiichi Pharmaceutical, Co., Ltd.
    • IIMURA Shin
    • Medicinal Chemistry Research Laboratory, Daiichi Pharmaceutical, Co., Ltd.
    • YONEDA Yoshiyuki
    • Medicinal Chemistry Research Laboratory, Daiichi Pharmaceutical, Co., Ltd.
    • SUGIMOTO Yuichi
    • Medicinal Chemistry Research Laboratory, Daiichi Pharmaceutical, Co., Ltd.
    • HORIUCHI Takao
    • Medicinal Chemistry Research Laboratory, Daiichi Pharmaceutical, Co., Ltd.
    • MURO Fumito
    • Medicinal Chemistry Research Laboratory, Daiichi Pharmaceutical, Co., Ltd.
    • OCHIAI Yuichi
    • Medicinal Chemistry Research Laboratory, Daiichi Pharmaceutical, Co., Ltd.
    • OGASAWARA Tomomi
    • Medicinal Chemistry Research Laboratory, Daiichi Pharmaceutical, Co., Ltd.
    • TSUBOKAWA Masao
    • New Product Research Laboratories III, Daiichi Pharmaceutical, Co., Ltd.
    • IIGOU Yutaka
    • New Product Research Laboratories III, Daiichi Pharmaceutical, Co., Ltd.
    • TAKAYAMA Gensuke
    • New Product Research Laboratories III, Daiichi Pharmaceutical, Co., Ltd.
    • TAIRA Tomoe
    • New Product Research Laboratories III, Daiichi Pharmaceutical, Co., Ltd.
    • TAKATA Yoshimi
    • New Product Research Laboratories III, Daiichi Pharmaceutical, Co., Ltd.
    • YOKOYAMA Mika
    • New Product Research Laboratories III, Daiichi Pharmaceutical, Co., Ltd.
    • TAKASHI Tohru
    • New Product Research Laboratories III, Daiichi Pharmaceutical, Co., Ltd.
    • NAKAYAMA Atsushi
    • Medicinal Chemistry Research Laboratory, Daiichi Pharmaceutical, Co., Ltd.
    • MACHINAGA Nobuo
    • Medicinal Chemistry Research Laboratory, Daiichi Pharmaceutical, Co., Ltd.

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 (IC_<50>=1.6nM each) and moderate lipophilicity (Log D=2.0, 1.8). Furthermore, 15e demonstrated efficacy in murine asthma model by an oral dose of 30mg/kg.

Journal

Chemical & pharmaceutical bulletin   [List of Volumes]

Chemical & pharmaceutical bulletin 54(11), 1515-1529, 2006-11-01  [Table of Contents]

The Pharmaceutical Society of Japan

References:  30

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Codes

  • NII Article ID (NAID) :
    110004836471
  • NII NACSIS-CAT ID (NCID) :
    AA00602100
  • Text Lang :
    ENG
  • Article Type :
    ART
  • ISSN :
    00092363
  • NDL Article ID :
    8516501
  • NDL Source Classification :
    ZS51(科学技術--薬学) // ZP1(科学技術--化学・化学工業)
  • NDL Call No. :
    Z53-D167
  • DOI :
    10.1248/cpb.54.1515
  • Databases :
    CJP  NDL  NII-ELS  J-STAGE