NR2B-Selective N-Methyl-d-aspartate Antagonists: Synthesis and Evaluation of 5-Substituted Benzimidazoles
- John A. McCauley
- ,
- Cory R. Theberge
- ,
- Joseph J. Romano
- ,
- Susan B. Billings
- ,
- Kenneth D. Anderson
- ,
- David A. Claremon
- ,
- Roger M. Freidinger
- ,
- Rodney A. Bednar
- ,
- Scott D. Mosser
- ,
- Stanley L. Gaul
- ,
- Thomas M. Connolly
- ,
- Cindra L. Condra
- ,
- Menghang Xia
- ,
- Michael E. Cunningham
- ,
- Bohumil Bednar
- ,
- Gary L. Stump
- ,
- Joseph J. Lynch
- ,
- Alison Macaulay
- ,
- Keith A. Wafford
- ,
- Kenneth S. Koblan
- , and
- Nigel J. Liverton
Abstract

Two classes of 5-substituted benzimidazoles were identified as potent antagonists of the NR2B subtype of the N-methyl-d-aspartate (NMDA) receptor. Selected compounds show very good selectivity versus the NR2A, NR2C, and NR2D subtypes of the NMDA receptor as well as versus hERG-channel activity and α1-adrenergic binding. Benzimidazole 37a shows excellent activity in the carrageenan-induced mechanical hyperalgesia assay in rats as well as good pharmacokinetic behavior in dogs.
*
To whom correspondence should be addressed. Phone: 215-652-4133. Fax: 215-652-3971. E-mail: [email protected].
†
Department of Medicinal Chemistry.
‡
Department of Molecular Pharmacology.
‖
Department of Pharmacology.
#
Department of Pharmacology, Merck Sharp & Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex, CM20 2QR, UK.
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