Referenced in: none

Automatically associated channels: Kv11.1

Title: Identification and characterization of 4-methylbenzyl 4-[(pyrimidin-2-ylamino)methyl]piperidine-1-carboxylate, an orally bioavailable, brain penetrant NR2B selective N-methyl-D-aspartate receptor antagonist.

Authors: 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 Lyle, Joseph J Lynch, John A McCauley, Scott D Mosser, Kevin T Nguyen, Gary L Stump, Hong Sun, Hao Wang, James Yergey, Kenneth S Koblan

Journal, date & volume: J. Med. Chem., 2007 Feb 22 , 50, 807-19

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/17249648

Abstract
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.