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.
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.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. nigel_liverton@merck.com
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Liverton
authors.forename: Rodney A
authors.initials: RA
authors.lastname: Bednar
authors.forename: Bohumil
authors.initials: B
authors.lastname: Bednar
authors.forename: John W
authors.initials: JW
authors.lastname: Butcher
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Claiborne
authors.forename: David A
authors.initials: DA
authors.lastname: Claremon
authors.forename: Michael
authors.initials: M
authors.lastname: Cunningham
authors.forename: Anthony G
authors.initials: AG
authors.lastname: DiLella
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Gaul
authors.forename: Brian E
authors.initials: BE
authors.lastname: Libby
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Lyle
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Lynch
authors.forename: John A
authors.initials: JA
authors.lastname: McCauley
authors.forename: Scott D
authors.initials: SD
authors.lastname: Mosser
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Nguyen
authors.forename: Gary L
authors.initials: GL
authors.lastname: Stump
authors.forename: Hong
authors.initials: H
authors.lastname: Sun
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: James
authors.initials: J
authors.lastname: Yergey
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Koblan
mesh_terms: D000284:Administration, Oral; D000700:Analgesics / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000978:Antiparkinson Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D001921:Brain / Q000378:metabolism*; D002460:Cell Line; D004285:Dogs; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism; D006801:Humans; D008297:Male; D010147:Pain Measurement; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: C518310:4-methylbenzyl 4-((pyrimidin-2-ylamino)methyl)piperidine-1-carboxylate; D000700:Analgesics; D000978:Antiparkinson Agents; C121001:NR2B NMDA receptor; D011743:Pyrimidines; D016194:Receptors, N-Methyl-D-Aspartate