Discovery of 3-substituted aminocyclopentanes as potent and orally bioavailable NR2B subtype-selective NMDA antagonists.
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.
['Layton|Mark E|ME|', 'Kelly|Michael J|MJ|', 'Rodzinak|Kevin J|KJ|', 'Sanderson|Philip E|PE|', 'Young|Steven D|SD|', 'Bednar|Rodney A|RA|', 'Dilella|Anthony G|AG|', 'McDonald|Terrence P|TP|', 'Wang|Hao|H|', 'Mosser|Scott D|SD|', 'Fay|John F|JF|', 'Cunningham|Michael E|ME|', 'Reiss|Duane R|DR|', 'Fandozzi|Christine|C|', 'Trainor|Nicole|N|', 'Liang|Annie|A|', 'Lis|Edward V|EV|', 'Seabrook|Guy R|GR|', 'Urban|Mark O|MO|', 'Yergey|James|J|', 'Koblan|Kenneth S|KS|']
D000284:Administration, Oral D000818:Animals D001578:Benzopyrans D001682:Biological Availability D002375:Catalepsy D003517:Cyclopentanes D004285:Dogs D055808:Drug Discovery D000072237:ERG1 Potassium Channel D051638:Ether-A-Go-Go Potassium Channels D018691:Excitatory Amino Acid Antagonists D005260:Female D006207:Half-Life D007202:Indicators and Reagents D007536:Isomerism D008026:Ligation D008253:Macaca mulatta D008297:Male D009437:Neuralgia D010069:Oxadiazoles D010300:Parkinson Disease D010880:Piperidines D011743:Pyrimidines D051381:Rats D017207:Rats, Sprague-Dawley D016194:Receptors, N-Methyl-D-Aspartate D013127:Spinal Nerves
NMDA neuropathic pain NR2B antagonist Parkinson’s disease