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.
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.
Liverton
Nigel J
NJ
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. nigel_liverton@merck.com
Bednar
Rodney A
RA
Bednar
Bohumil
B
Butcher
John W
JW
Claiborne
Christopher F
CF
Claremon
David A
DA
Cunningham
Michael
M
DiLella
Anthony G
AG
Gaul
Stanley L
SL
Libby
Brian E
BE
Lyle
Elizabeth A
EA
Lynch
Joseph J
JJ
McCauley
John A
JA
Mosser
Scott D
SD
Nguyen
Kevin T
KT
Stump
Gary L
GL
Sun
Hong
H
Wang
Hao
H
Yergey
James
J
Koblan
Kenneth S
KS
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
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