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

• Published in: Journal of medicinal chemistry Vol. 50; no. 4; pp. 807 - 819
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 22.02.2007; Amer Chemical Soc
• Subjects: Administration, Oral; Analgesics; Analgesics - chemical synthesis; Analgesics - pharmacokinetics; Analgesics - pharmacology; Animals; Antiparkinson Agents - chemical synthesis; Antiparkinson Agents - pharmacokinetics; Antiparkinson Agents - pharmacology; Biological and medical sciences; Biological Availability; Brain - metabolism; Cell Line; Chemistry, Medicinal; Dogs; Female; Frontal Lobe - metabolism; Glutamatergic system (aspartate and other excitatory aminoacids); Humans; Life Sciences & Biomedicine; Male; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pain Measurement; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Pyrimidines - chemical synthesis; Pyrimidines - pharmacokinetics; Pyrimidines - pharmacology; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Science & Technology; Structure-Activity Relationship; NEUROPATHIC PAIN; LOCALIZATION; IN-VITRO; POSTHERPETIC NEURALGIA; GLUTAMATE; SPINAL NERVE LIGATION; NMDA; EXPRESSION; POTASSIUM CHANNEL; SUBUNIT; Intravenous administration; Rat; Parkinson disease; Glutamate receptor; Selectivity; Blood brain barrier; Hyperalgesia; Structure activity relation; Piperidine derivatives; Degenerative disease; Antagonist; Rodentia; Oral administration; Bioavailability; In vitro; In vivo; Vertebrata; Mammalia; Analgesic; Penetration; Animal; Carboxylate; Pyrimidine derivatives; Pharmacokinetics; NMDA receptor
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm060983w

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.