Fused tricyclic mGluR1 antagonists for the treatment of neuropathic pain

• Published in: Bioorganic & medicinal chemistry letters Vol. 22; no. 4; pp. 1575 - 1578
• Main Authors: Bennett, Chad E., Burnett, Duane A., Greenlee, William J., Knutson, Chad E., Korakas, Peter, Li, Cheng, Tulshian, Deen, Wu, Wen-Lian, Bertorelli, Rosalia, Fredduzzi, Silva, Grilli, Mariagrazia, Lozza, Gianluca, Reggiani, Angelo, Veltri, Alessio
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.02.2012; Elsevier
• Subjects: Administration, Oral; Analgesics - pharmacology; Animals; Antagonists; Biological and medical sciences; Cells, Cultured; Cyclization; Fused tricyclic pyridones; Glutamic acid receptors (metabotropic); GPCR; Humans; Inhibitory Concentration 50; Isoenzymes; isozymes; Medical sciences; mGluR1 (metabotropic glutamate receptor 1); Molecular Structure; Neuralgia - drug therapy; Neuropathic pain; Neuropathy; pain; Pharmacology. Drug treatments; Protein Binding - drug effects; Pyridones - chemical synthesis; Pyridones - chemistry; Pyridones - pharmacology; Rats; Receptors, Metabotropic Glutamate - antagonists & inhibitors; Spinal nerve ligation (SNL); GPCR; mGluR1 (metabotropic glutamate receptor 1); Fused tricyclic pyridones; Spinal nerve ligation (SNL); Neuropathic pain; Pyridone derivatives; Group I mglu glutamate receptor; Chemical structure; mglu1 glutamate receptor; Glutamate receptor; chemical ligation; Tricyclic compound; In vitro; Spinal nerve; Pyridine derivatives; Analgesic; Metabotropic receptor; G protein coupled receptor; Antagonist; mGluR1 (metabotropic glutamate receptor 1 )
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.12.131

A series of fused tricyclic mGluR1 antagonists containing a pyridone ring were synthesized. In vitro, these antagonists were potent against both human and rat isozymes, as well as selective for inhibiting mGluR1 over mGluR5. When dosed orally, several examples were active in vivo in a rat SNL test.