1138432-16-2Relevant academic research and scientific papers
A novel and potent VLA-4 antagonist based on trans-4-substituted cyclohexanecarboxylic acid
Muro, Fumihito,Iimura, Shin,Yoneda, Yoshiyuki,Chiba, Jun,Watanabe, Toshiyuki,Setoguchi, Masaki,Takayama, Gensuke,Yokoyama, Mika,Takashi, Tohru,Nakayama, Atsushi,Machinaga, Nobuo
experimental part, p. 1232 - 1243 (2009/08/15)
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, IC50 = 19 nM) in VLA-4 inhibitory activity compared to 1 (IC50 = 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 (IC50 = 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.
