title: A novel, potent, and orally active VLA-4 antagonist with good aqueous solubility: trans-4-[1-[[2-(5-Fluoro-2-methylphenylamino)-7-fluoro-6-benzoxazolyl]acetyl]-(5S)-[methoxy(methyl)amino]methyl-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid.
abstract: We have carried out the optimization of substituents at the C-3 or the C-5 position on the pyrrolidine ring of VLA-4 antagonist 3 with 2-(phenylamino)-7-fluorobenzoxazolyl moiety for the purpose of improving in vivo efficacy while maintaining good aqueous solubility. As a result, we successfully increased in vitro activity in the presence of 3% human serum albumin and achieved an exquisite lipophilic and hydrophilic balance of compounds suitable for oral administrative regimen. The modification resulted in the identification of zwitterionic compound 7n with (5S)-[methoxy(methyl)amino]methylpyrrolidine, which significantly alleviated bronchial hyper-responsiveness to acetylcholine chloride at 12.5mg/kg, p.o. in a murine asthma model and showed favorable aqueous solubility (JP1, 89 μg/mL; JP2, 462 μg/mL). Furthermore, this compound showed good oral bioavailability (F=54%) in monkeys.
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; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology; D001682:Biological Availability; D001980:Bronchi / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D003509:Cyclohexanecarboxylic Acids / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology; D005260:Female; D000882:Haplorhini; D006801:Humans; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D011759:Pyrrolidines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D012995:Solubility; D014867:Water / Q000737:chemistry
chemical_list: D000893:Anti-Inflammatory Agents; D003509:Cyclohexanecarboxylic Acids; D039041:Integrin alpha4beta1; D011759:Pyrrolidines; D014867:Water; C044895:cyclohexanecarboxylic acid; C032519:pyrrolidine