Identification and Characterization of 4-Methylbenzyl 4-[(Pyrimidin-2-ylamino)methyl]piperidine-1-carboxylate, an Orally Bioavailable, Brain Penetrant NR2B Selective N-Methyl-D<

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• 作者：Nigel J. Liverton ; Rodney A. Bednar ; Bohumil Bednar ; John W. Butcher ; Christopher F. Claiborne ; David A. Claremon ; Michael Cunningham ; Anthony G. DiLella ; Stanley L. Gaul ; Brian E. Libby ; Elizabeth A
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：February 22, 2007
• 年：2007
• 卷：50
• 期：4
• 页码：807 - 819
• 全文大小：194K
• 年卷期：v.50,no.4(February 22, 2007)
• ISSN：1520-4804

文摘

The discovery of a novel series of NR2B subtype selective N-methyl-D-aspartate (NMDA) antagonists isreported. Initial optimization of a high-throughput screening lead afforded an aminopyridine derivative 13with significant NR2B antagonist potency but limited selectivity over hERG-channel and other off-targetactivities. Further structure-activity studies on the aminoheterocycle moiety and optimization of the carbamateled to the highly potent 2-aminopyrimidine derivative 20j with a significantly improved off-target activityprofile and oral bioavailability in multiple species coupled with good brain penetration. Compound 20jdemonstrated efficacy in in vivo rodent models of antinociception, allodynia, and Parkinson's disease.