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.
MeSH terms
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Administration, Oral
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Analgesics / chemical synthesis*
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Analgesics / pharmacokinetics
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Analgesics / pharmacology
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Animals
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Antiparkinson Agents / chemical synthesis
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Antiparkinson Agents / pharmacokinetics
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Antiparkinson Agents / pharmacology
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Biological Availability
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Brain / metabolism*
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Cell Line
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Dogs
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Female
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Frontal Lobe / metabolism
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Humans
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Male
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Pain Measurement
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Pyrimidines / chemical synthesis*
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Pyrimidines / pharmacokinetics
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Pyrimidines / pharmacology
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Radioligand Assay
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Rats
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Rats, Sprague-Dawley
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Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
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Structure-Activity Relationship
Substances
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4-methylbenzyl 4-((pyrimidin-2-ylamino)methyl)piperidine-1-carboxylate
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Analgesics
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Antiparkinson Agents
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NR2B NMDA receptor
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Pyrimidines
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Receptors, N-Methyl-D-Aspartate