title: Identification of trans-4-[1-[[7-fluoro-2-(1-methyl-3-indolyl)-6-benzoxazolyl]acetyl]-(4S)-fluoro-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid as a potent, orally active VLA-4 antagonist.
abstract: For the purpose of obtaining orally potent VLA-4 inhibitors, we have carried out structural modification of the (N'-phenylureido)phenyl group in compound 1, where the group was found to be attributed to poor pharmacokinetic profile in our previous research. Through modification, we have identified several compounds with both potent in vitro activity and improved oral exposure. In particular, compound 7e with 7-fluoro-2-(1-methyl-1H-indol-3-yl)-1,3-benzoxazolyl group as a novel replacement of the (N'-phenylureido)phenyl group significantly inhibited eosinophil infiltration into bronchoalveolar lavage fluid at 15mg/kg in an Ascaris-antigen-induced murine bronchial inflammatory model, and its efficacy was comparable to that of the anti-mouse α(4) antibody (R1-2).
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd, 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. setoguchi.masaki.d4@daiichisankyo.co.jp
authors.forename: Masaki
authors.initials: M
authors.lastname: Setoguchi
authors.forename: Shin
authors.initials: S
authors.lastname: Iimura
authors.forename: Yuuichi
authors.initials: Y
authors.lastname: Sugimoto
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Yoneda
authors.forename: Jun
authors.initials: J
authors.lastname: Chiba
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Watanabe
authors.forename: Fumihito
authors.initials: F
authors.lastname: Muro
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Iigo
authors.forename: Gensuke
authors.initials: G
authors.lastname: Takayama
authors.forename: Mika
authors.initials: M
authors.lastname: Yokoyama
authors.forename: Tomoe
authors.initials: T
authors.lastname: Taira
authors.forename: Misato
authors.initials: M
authors.lastname: Aonuma
authors.forename: Tohru
authors.initials: T
authors.lastname: Takashi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nakayama
authors.forename: Nobuo
authors.initials: N
authors.lastname: Machinaga
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology; D001980:Bronchi / Q000187:drug effects / Q000276:immunology; D018893:Bronchoalveolar Lavage; D002460:Cell Line; D003509:Cyclohexanecarboxylic Acids / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology; D005260:Female; D006801:Humans; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D051379:Mice; D008807:Mice, Inbred BALB C; D013329:Structure-Activity Relationship
chemical_list: D003509:Cyclohexanecarboxylic Acids; D039041:Integrin alpha4beta1; C044895:cyclohexanecarboxylic acid