title: A novel and potent VLA-4 antagonist based on trans-4-substituted cyclohexanecarboxylic acid.
abstract: During the course of our study, it was revealed that the poor pharmacokinetic properties of a series of benzoic acid derivatives such as 1 should be attributed to the diphenylurea moiety. Thus, we replaced the diphenylurea moiety in 1 with a 2-(2-methylphenylamino)benzoxazole moiety which mimics the diphenylurea structure. However, this modification resulted in a significant decrease (3, IC(50)=19 nM) in VLA-4 inhibitory activity compared to 1 (IC(50)=1.6 nM). To address this discrepancy, we worked on optimization of the carboxylic acid moiety in compound 3. As a result, our efforts have led to the discovery of trans-4-substituted cyclohexanecarboxylic acid derivative 11b (IC(50)=2.8 nM) as a novel and potent VLA-4 antagonist. In addition, compound 11b exhibited favorable pharmacokinetic properties (CL=3.3 ml/min/kg, F=51%) in rats.
authors.affiliation: Medicinal Chemistry Research Laboratories II, Daiichi Sankyo Co., Ltd, 1-16-13, Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan. muro.fumihito.iy@daiichisankyo.co.jp
authors.forename: Fumihito
authors.initials: F
authors.lastname: Muro
authors.forename: Shin
authors.initials: S
authors.lastname: Iimura
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: Masaki
authors.initials: M
authors.lastname: Setoguchi
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: D000818:Animals; D001583:Benzoxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D003509:Cyclohexanecarboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D020128:Inhibitory Concentration 50; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D008968:Molecular Conformation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: C539860:4-((2-(2-methylphenylamino)-6-benzoxazolylacetyl)-4-fluoro-2-pyrrolidinylmethoxy)cyclohexanecarboxylic acid; D001583:Benzoxazoles; D003509:Cyclohexanecarboxylic Acids; D039041:Integrin alpha4beta1; C044895:cyclohexanecarboxylic acid