2. Academic Validation
  3. Discovery of 3-substituted aminocyclopentanes as potent and orally bioavailable NR2B subtype-selective NMDA antagonists

Discovery of 3-substituted aminocyclopentanes as potent and orally bioavailable NR2B subtype-selective NMDA antagonists

  • ACS Chem Neurosci. 2011 Jul 20;2(7):352-62. doi: 10.1021/cn200013d.
Mark E Layton 1,  Michael J Kelly 3rd,  Kevin J Rodzinak,  Philip E Sanderson,  Steven D Young,  Rodney A Bednar,  Anthony G Dilella,  Terrence P McDonald,  Hao Wang,  Scott D Mosser,  John F Fay,  Michael E Cunningham,  Duane R Reiss,  Christine Fandozzi,  Nicole Trainor,  Annie Liang,  Edward V Lis,  Guy R Seabrook,  Mark O Urban,  James Yergey,  Kenneth S Koblan
Affiliations

Affiliation

  • 1 Departments of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. mark_layton@merck.com
PMID: 22816022 DOI: 10.1021/cn200013d
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.

Keywords

NMDA; NR2B antagonist; Parkinson’s disease; neuropathic pain.

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