Discovery and SAR of orally active tri- and tetracyclic mGluR1 antagonists

MEDI 454

Duane A. Burnett, duane.burnett@spcorp.com1, Deen Tulshian1, Stephanie Cooke, stephanie.cooke@spcorp.com1, Julius Matasi, julius.matasi@spcorp.com1, Peter Korakas1, Lisa S. Silverman1, Thavalakulamgara K Sasikumar1, Wen-Lian Wu, wen-lian.wu@spcorp.com1, Chad Bennett1, Chad Knutson, chad.knutson@spcorp.com1, William J Greenlee, william.greenlee@spcorp.com2, A. Reggiani3, A. Veltri3, R. Bertorelli3, S. Fredduzzi3, G. Lozza3, G. Tarozzo3, C. Foglia3, and M. Grilli3. (1) CV/CNS Chemical Research, Schering-Plough Research Institute, 2015 Galloping Hill Road, MS 2800, Kenilworth, NJ 07033, (2) Department of Chemical Research-CV/CNS, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, (3) Department of Neurobiological Research, Schering-Plough Research Institute, San Raffali Science Park, Milan, Italy
Abstract: The role of metabotropic glutamate receptors in the perception of pain, in particular neuropathic pain, has been well established. A high affinity tricyclic mGluR1 antagonist was discovered during the course of a high throughput screen at SPRI. Optimization of the peripheral substituents and the core heterocycle led to the discovery of a number of highly potent, orally active mGluR1 antagonists with high selectivity over other metabotropic glutamate receptors. These compounds are very effective in animal models of neuropathic pain, including the spinal nerve ligation model. An overview of this discovery and SAR efforts will be presented.
 

General Oral Session
9:00 AM-12:20 PM, Thursday, August 23, 2007 BCEC -- 210B, Oral

Division of Medicinal Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007