Liverton Nigel J, Bednar Rodney A, Bednar Bohumil, Butcher John W, Claiborne Christopher F, Claremon David A, Cunningham Michael, DiLella Anthony G, Gaul Stanley L, Libby Brian E, Lyle Elizabeth A, Lynch Joseph J, McCauley John A, Mosser Scott D, Nguyen Kevin T, Stump Gary L, Sun Hong, Wang Hao, Yergey James, Koblan Kenneth S
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
J Med Chem. 2007 Feb 22;50(4):807-19. doi: 10.1021/jm060983w. Epub 2007 Jan 24.
The discovery of a novel series of NR2B subtype selective N-methyl-d-aspartate (NMDA) antagonists is reported. Initial optimization of a high-throughput screening lead afforded an aminopyridine derivative 13 with significant NR2B antagonist potency but limited selectivity over hERG-channel and other off-target activities. Further structure-activity studies on the aminoheterocycle moiety and optimization of the carbamate led to the highly potent 2-aminopyrimidine derivative 20j with a significantly improved off-target activity profile and oral bioavailability in multiple species coupled with good brain penetration. Compound 20j demonstrated efficacy in in vivo rodent models of antinociception, allodynia, and Parkinson's disease.
报道了一系列新型NR2B亚型选择性N-甲基-D-天冬氨酸（NMDA）拮抗剂的发现。对高通量筛选先导化合物进行初步优化，得到氨基吡啶衍生物13，其具有显著的NR2B拮抗剂活性，但对人乙醚相关基因（hERG）通道和其他脱靶活性的选择性有限。对氨基杂环部分进行进一步的构效关系研究并优化氨基甲酸酯，得到了高效的2-氨基嘧啶衍生物20j，其脱靶活性显著改善，在多个物种中具有良好的口服生物利用度，且脑渗透性良好。化合物20j在抗伤害感受、异常性疼痛和帕金森病的体内啮齿动物模型中显示出疗效。
