NR2B-selective N-methyl-D-aspartate antagonists: synthesis and evaluation of 5-substituted benzimidazoles.
Two classes of 5-substituted benzimidazoles were identified as potent antagonists of the NR2B subtype of the N-methyl-d-aspartate (NMDA) receptor. Selected compounds show very good selectivity versus the NR2A, NR2C, and NR2D subtypes of the NMDA receptor as well as versus hERG-channel activity and alpha(1)-adrenergic binding. Benzimidazole 37a shows excellent activity in the carrageenan-induced mechanical hyperalgesia assay in rats as well as good pharmacokinetic behavior in dogs.
McCauley
John A
JA
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. john_mccauley@merck.com
Theberge
Cory R
CR
Romano
Joseph J
JJ
Billings
Susan B
SB
Anderson
Kenneth D
KD
Claremon
David A
DA
Freidinger
Roger M
RM
Bednar
Rodney A
RA
Mosser
Scott D
SD
Gaul
Stanley L
SL
Connolly
Thomas M
TM
Condra
Cindra L
CL
Xia
Menghang
M
Cunningham
Michael E
ME
Bednar
Bohumil
B
Stump
Gary L
GL
Lynch
Joseph J
JJ
Macaulay
Alison
A
Wafford
Keith A
KA
Koblan
Kenneth S
KS
Liverton
Nigel J
NJ
D000700:Analgesics / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002351:Carrageenan; D002460:Cell Line; D004285:Dogs; D005260:Female; D006801:Humans; D006930:Hyperalgesia / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy; D066298:In Vitro Techniques; D008297:Male; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000502:physiology; D013329:Structure-Activity Relationship
D000700:Analgesics; D001562:Benzimidazoles; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D002351:Carrageenan; D002118:Calcium