一种基于反式-4-取代环己烷羧酸的新型强效VLA-4拮抗剂。
A novel and potent VLA-4 antagonist based on trans-4-substituted cyclohexanecarboxylic acid.
作者信息
Muro Fumihito, Iimura Shin, Yoneda Yoshiyuki, Chiba Jun, Watanabe Toshiyuki, Setoguchi Masaki, Takayama Gensuke, Yokoyama Mika, Takashi Tohru, Nakayama Atsushi, Machinaga Nobuo
机构信息
Medicinal Chemistry Research Laboratories II, Daiichi Sankyo Co., Ltd, 1-16-13, Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.
出版信息
Bioorg Med Chem. 2009 Feb 1;17(3):1232-43. doi: 10.1016/j.bmc.2008.12.026. Epub 2008 Dec 24.
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.
在我们的研究过程中，发现一系列苯甲酸衍生物（如化合物1）的药代动力学性质较差应归因于二苯基脲部分。因此，我们将化合物1中的二苯基脲部分替换为模拟二苯基脲结构的2-(2-甲基苯基氨基)苯并恶唑部分。然而，与化合物1（IC50 = 1.6 nM）相比，这种修饰导致VLA-4抑制活性显著降低（化合物3，IC50 = 19 nM）。为了解决这一差异，我们致力于优化化合物3中的羧酸部分。结果，我们的努力导致发现反式-4-取代环己烷羧酸衍生物11b（IC50 = 2.8 nM）作为一种新型强效VLA-4拮抗剂。此外，化合物11b在大鼠中表现出良好的药代动力学性质（CL = 3.3 ml/min/kg，F = 51%）。
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