title: Discovery of 3-substituted aminocyclopentanes as potent and orally bioavailable NR2B subtype-selective NMDA antagonists.
abstract: A series of 3-substituted aminocyclopentanes has been identified as highly potent and selective NR2B receptor antagonists. Incorporation of a 1,2,4-oxadiazole linker and substitution of the pendant phenyl ring led to the discovery of orally bioavailable analogues that showed efficient NR2B receptor occupancy in rats. Unlike nonselective NMDA antagonists, the NR2B-selective antagonist 22 showed no adverse affects on motor coordination in the rotarod assay at high dose. Compound 22 was efficacious following oral administration in a spinal nerve ligation model of neuropathic pain and in an acute model of Parkinson's disease in a dose dependent manner.
authors: Departments of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. mark_layton@merck.com
authors: Mark E
authors: ME
authors: Layton
authors: Michael J
authors: MJ
authors: Kelly
authors: Kevin J
authors: KJ
authors: Rodzinak
authors: Philip E
authors: PE
authors: Sanderson
authors: Steven D
authors: SD
authors: Young
authors: Rodney A
authors: RA
authors: Bednar
authors: Anthony G
authors: AG
authors: Dilella
authors: Terrence P
authors: TP
authors: McDonald
authors: Hao
authors: H
authors: Wang
authors: Scott D
authors: SD
authors: Mosser
authors: John F
authors: JF
authors: Fay
authors: Michael E
authors: ME
authors: Cunningham
authors: Duane R
authors: DR
authors: Reiss
authors: Christine
authors: C
authors: Fandozzi
authors: Nicole
authors: N
authors: Trainor
authors: Annie
authors: A
authors: Liang
authors: Edward V
authors: EV
authors: Lis
authors: Guy R
authors: GR
authors: Seabrook
authors: Mark O
authors: MO
authors: Urban
authors: James
authors: J
authors: Yergey
authors: Kenneth S
authors: KS
authors: Koblan
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001578:Benzopyrans / Q000378:metabolism; D001682:Biological Availability; D002375:Catalepsy / Q000139:chemically induced / Q000188:drug therapy; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000494:pharmacology*; D004285:Dogs; D055808:Drug Discovery / Q000379:methods*; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D005260:Female; D006207:Half-Life; D007202:Indicators and Reagents; D007536:Isomerism; D008026:Ligation; D008253:Macaca mulatta; D008297:Male; D009437:Neuralgia / Q000188:drug therapy; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D010300:Parkinson Disease / Q000188:drug therapy; D010880:Piperidines / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013127:Spinal Nerves / Q000473:pathology
chemical_list: D001578:Benzopyrans; D003517:Cyclopentanes; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D018691:Excitatory Amino Acid Antagonists; D007202:Indicators and Reagents; C579629:N-(3-(3-(4-methylbenzyl)-1,2,4-oxadiazol-5-yl)cyclopentyl)-1H-pyrazolo(3,4-d)pyrimidin-4-amine; C121001:NR2B NMDA receptor; D010069:Oxadiazoles; D010880:Piperidines; D011743:Pyrimidines; D016194:Receptors, N-Methyl-D-Aspartate; C087257:L 706000