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  • 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.
    Author: Liverton NJ, Bednar RA, Bednar B, Butcher JW, Claiborne CF, Claremon DA, Cunningham M, DiLella AG, Gaul SL, Libby BE, Lyle EA, Lynch JJ, McCauley JA, Mosser SD, Nguyen KT, Stump GL, Sun H, Wang H, Yergey J, Koblan KS.
    Journal: J Med Chem; 2007 Feb 22; 50(4):807-19. PubMed ID: 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.
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