title: Synthesis and biological evaluation of benzoic acid derivatives as potent, orally active VLA-4 antagonists.
abstract: A series of benzoic acid derivatives was synthesized as VLA-4 antagonists. Introduction of chlorine or bromine into the 3-position on the central benzene of the diphenylurea portion as in lead compound 2 led to improvement in the pharmacokinetic properties. In particular, 12l demonstrated an acceptable plasma clearance and bioavailability in mice and rats as well as dogs (mice, CL=18.5 ml/min/kg,F=28%; rats, CL=5.2 ml/min/kg,F=36%; dogs, CL=3.6 ml/min/kg,F=55%). Additionally, 12l exhibited potent activity with an IC50 value of 0.51 nM and efficacy by oral administration at a dosage of 10 mg/kg in a rat pleurisy model.
authors.affiliation: Medicinal Chemistry Research Laboratory, Daiichi Pharmaceutical, Co., Ltd, 16-13, Kitakasai 1-chome, Edogawa-ku, Tokyo 134-8630, 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: Toshiyuki
authors.initials: T
authors.lastname: Watanabe
authors.forename: Fumito
authors.initials: F
authors.lastname: Muro
authors.forename: Masao
authors.initials: M
authors.lastname: Tsubokawa
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Iigou
authors.forename: Atsushi
authors.initials: A
authors.lastname: Satoh
authors.forename: Gensuke
authors.initials: G
authors.lastname: Takayama
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; D001565:Benzoates / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology; D004195:Disease Models, Animal; D004285:Dogs; D007249:Inflammation / Q000188:drug therapy; D020128:Inhibitory Concentration 50; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D051379:Mice; D010599:Pharmacokinetics; D010998:Pleurisy / Q000188:drug therapy; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D001565:Benzoates; D039041:Integrin alpha4beta1