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Article

A Pyridazine Series of α2/α3 Subtype Selective GABA_A Agonists for the Treatment of Anxiety

Supporting Info

Richard T. Lewis,* Wesley P. Blackaby, Timothy Blackburn, Andrew S. R. Jennings, Andrew Pike, Rowan A. Wilson, David J. Hallett, Susan M. Cook, Pushpinder Ferris, George R. Marshall, David S. Reynolds, Wayne F. A. Sheppard, Alison J. Smith, Bindi Sohal, Joanna Stanley, Spencer J. Tye, Keith A. Wafford, and John R. Atack

The Neuroscience Research Centre, Merck Sharp & Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex, CM20 2QR, United Kingdom

J. Med. Chem., 2006, 49 (8), pp 2600–2610

DOI: 10.1021/jm051144x

Publication Date (Web): March 22, 2006

To whom correspondence should be addressed. Tel +44 (0)1279 440000; Fax +44 (0) 1279 440390; e-mail: richard_t_lewis@btinternet.com.

Abstract

The development of a series of GABA_A α2/α3 subtype selective pyridazine based benzodiazepine site agonists as anxiolytic agents with reduced sedative/ataxic potential is described, including the discovery of 16, a remarkably α3-selective compound ideal for in vivo study. These ligands are antagonists at the α1 subtype, with good CNS penetration and receptor occupancy, and excellent oral bioavailability.

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Published In Issue April 20, 2006
Received November 15, 2005

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Article

A Pyridazine Series of α2/α3 Subtype Selective GABA_A Agonists for the Treatment of Anxiety