1. Discovery of 3-substituted aminocyclopentanes as potent and orally bioavailable NR2B subtype-selective NMDA antagonists.
- Author
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Layton ME, Kelly MJ 3rd, Rodzinak KJ, Sanderson PE, Young SD, Bednar RA, Dilella AG, McDonald TP, Wang H, Mosser SD, Fay JF, Cunningham ME, Reiss DR, Fandozzi C, Trainor N, Liang A, Lis EV, Seabrook GR, Urban MO, Yergey J, and Koblan KS
- Subjects
- Administration, Oral, Animals, Benzopyrans metabolism, Biological Availability, Catalepsy chemically induced, Catalepsy drug therapy, Dogs, ERG1 Potassium Channel, Ether-A-Go-Go Potassium Channels antagonists & inhibitors, Ether-A-Go-Go Potassium Channels metabolism, Female, Half-Life, Indicators and Reagents, Isomerism, Ligation, Macaca mulatta, Male, Neuralgia drug therapy, Parkinson Disease drug therapy, Piperidines metabolism, Rats, Rats, Sprague-Dawley, Spinal Nerves pathology, Cyclopentanes chemical synthesis, Cyclopentanes pharmacology, Drug Discovery methods, Excitatory Amino Acid Antagonists chemical synthesis, Excitatory Amino Acid Antagonists pharmacology, Oxadiazoles chemical synthesis, Oxadiazoles pharmacology, Pyrimidines chemical synthesis, Pyrimidines pharmacology, Receptors, N-Methyl-D-Aspartate antagonists & inhibitors
- 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.
- Published
- 2011
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