title: 4-(Pyrrolidinyl)methoxybenzoic acid derivatives as a potent, orally active VLA-4 antagonist.
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 (IC50 = 1.6 nM each) and moderate lipophilicity (Log D = 2.0, 1.8). Furthermore, 15e demonstrated efficacy in murine asthma model by an oral dose of 30 mg/kg.
authors.affiliation: Medicinal Chemistry Research Laboratory, Daiichi Pharmaceutical, Co., Ltd., Tokyo, Japan. chiba2mk@daiichipharm.co.jp
authors.forename: Jun
authors.initials: J
authors.lastname: Chiba
authors.forename: Shin
authors.initials: S
authors.lastname: Iimura
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Yoneda
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugimoto
authors.forename: Takao
authors.initials: T
authors.lastname: Horiuchi
authors.forename: Fumito
authors.initials: F
authors.lastname: Muro
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Ochiai
authors.forename: Tomomi
authors.initials: T
authors.lastname: Ogasawara
authors.forename: Masao
authors.initials: M
authors.lastname: Tsubokawa
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Iigou
authors.forename: Gensuke
authors.initials: G
authors.lastname: Takayama
authors.forename: Tomoe
authors.initials: T
authors.lastname: Taira
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Takata
authors.forename: Mika
authors.initials: M
authors.lastname: Yokoyama
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*; D001565:Benzoates / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D002463:Cell Membrane Permeability / Q000187:drug effects; D004195:Disease Models, Animal; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D062425:Hydroxybenzoate Ethers; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D007668:Kidney / Q000166:cytology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008968:Molecular Conformation; D011759:Pyrrolidines / Q000737:chemistry*; D011760:Pyrrolidinones / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C516633:4-(Pyrrolidinyl)methoxybenzoic acid; D001565:Benzoates; D062425:Hydroxybenzoate Ethers; D039041:Integrin alpha4beta1; D011759:Pyrrolidines; D011760:Pyrrolidinones