Synthesis and evaluation of novel tricyclic benzo[4.5]cyclohepta[1.2]pyridine derivatives as NMDA/NR2B antagonists.
A novel series of annulated tricyclic compounds was synthesized and evaluated as NMDA/NR2B antagonists. Structure-activity development was directed towards in vitro optimization of NR2B activity and selectivity over the hERG K(+) channel. Preferred compounds were subsequently evaluated for selectivity in an alpha(1)-adrenergic receptor binding counter-screen and a cell-based assay of NR2B activity.
McIntyre
Charles J
CJ
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. cjmcintyc@yahoo.com
McCauley
John A
JA
Bednar
Bohumil
B
Bednar
Rodney A
RA
Butcher
John W
JW
Claremon
David A
DA
Cunningham
Michael E
ME
Freidinger
Roger M
RM
Gaul
Stanley L
SL
Homnick
Carl F
CF
Koblan
Ken S
KS
Mosser
Scott D
SD
Romano
Joseph J
JJ
Liverton
Nigel J
NJ
D001567:Benzocycloheptenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D006801:Humans; D018377:Neurotransmitter Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D001567:Benzocycloheptenes; D051638:Ether-A-Go-Go Potassium Channels; C496884:KCNH1 protein, human; C121001:NR2B NMDA receptor; D018377:Neurotransmitter Agents; D011725:Pyridines; D016194:Receptors, N-Methyl-D-Aspartate