A novel and potent VLA-4 antagonist based on trans-4-substituted cyclohexanecarboxylic acid.
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.
Muro
Fumihito
F
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
Iimura
Shin
S
Yoneda
Yoshiyuki
Y
Chiba
Jun
J
Watanabe
Toshiyuki
T
Setoguchi
Masaki
M
Takayama
Gensuke
G
Yokoyama
Mika
M
Takashi
Tohru
T
Nakayama
Atsushi
A
Machinaga
Nobuo
N
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
C539860:4-((2-(2-methylphenylamino)-6-benzoxazolylacetyl)-4-fluoro-2-pyrrolidinylmethoxy)cyclohexanecarboxylic acid; D001583:Benzoxazoles; D003509:Cyclohexanecarboxylic Acids; D039041:Integrin alpha4beta1; C044895:cyclohexanecarboxylic acid