From arylureas to biarylamides to aminoquinazolines: Discovery of a novel, potent TRPV1 (VR1) antagonist

MEDI 315

Xiaozhang Zheng1, Charles A. Blum, cblum@nrgn.com1, Kevin J. Hodgetts1, Harry Brielmann1, Alan J. Hutchison1, Bertrand L. Chenard1, Frank Burkamp2, A. Brian Jones2, Peter Blurton2, Robert Clarkson2, Jayaraman Chandrasekhar1, Rajagopal Bakthavatchalam1, Stéphane De Lombaert1, Marci Crandall1, David Matson1, and Daniel Cortright1. (1) Neurogen Corp, 35 N. E. Industrial Rd, Branford, CT 06405, (2) Merck Sharp & Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Harlow, Essex CM20 2QR, U.K, The Neuroscience Research Centre, Terlings Park, Harlow, United Kingdom
Derivatives of N,4-diphenylpiperazine-1-carboxamide (aryl-ureas) are potent TRPV1 (VR1) antagonists but are often metabolically labile and demonstrate poor oral bioavailability. Bioisosteric replacement of the piperazine (B-ring) with an aryl-ring was feasible with minimal loss of potency at the VR1 receptor. Preparation of a conformationally constrained analog resulted in the discovery of the aminoquinazolines. This novel VR1 antagonist template exhibits improved in vitro potency and oral bioavailability relative to the corresponding urea or carboxamide compounds.

 

Antagonists of TRP Channels and Vanilloid Receptors
1:30 PM-4:55 PM, Wednesday, 13 September 2006 Moscone Center -- Room 102, Oral

Division of Medicinal Chemistry

The 232nd ACS National Meeting, San Francisco, CA, September 10-14, 2006