Synthesis and SAR development of novel mGluR1 antagonists for the treatment of chronic pain.

Abstract

High throughput screening identified the pyridothienopyrimidinone 1 as a ligand for the metabotropic glutamate receptor 1 (mGluR1=10 nM). Compound 1 has an excellent in vivo profile; however, it displays unfavorable pharmacokinetic issues and metabolic stability. Therefore, using 1 as a template, novel analogues (10i) were prepared. These analogues displayed improved oral exposure and activity in the Spinal Nerve Ligation (SNL) pain model.

• Authors: Stephanie Brumfield, Peter Korakas, Lisa S Silverman, Deen Tulshian, Julius J Matasi, Li Qiang, Chad E Bennett, Duane A Burnett, William J Greenlee, Chad E Knutson, Wen-Lian Wu, T K Sasikumar, Martin Domalski, Rosalia Bertorelli, Mariagrazia Grilli, Gianluca Lozza, Angelo Reggiani, Cheng Li
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 22 Issue 23 Pg. 7223-6 (Dec 01 2012) ISSN: 1464-3405 [Electronic] England
• PMID: 23084894 (Publication Type: Journal Article)
• Copyright: Copyright © 2012 Elsevier Ltd. All rights reserved.

Chemical References

• Heterocyclic Compounds, 3-Ring
• Pyrimidinones
• Receptors, Metabotropic Glutamate
• Thiophenes
• metabotropic glutamate receptor type 1

Topics

• Administration, Oral
• Animals
• Chronic Pain (drug therapy)
• Disease Models, Animal
• Heterocyclic Compounds, 3-Ring (chemical synthesis, chemistry, therapeutic use)
• Humans
• Pyrimidinones (chemical synthesis, chemistry, therapeutic use)
• Rats
• Receptors, Metabotropic Glutamate (antagonists & inhibitors, metabolism)
• Structure-Activity Relationship
• Thiophenes (chemical synthesis, chemistry, therapeutic use)