Discovery of isoxazole voltage gated sodium channel blockers for treatment of chronic pain

• Published in: Bioorganic & medicinal chemistry letters Vol. 19; no. 18; pp. 5334 - 5338
• Main Authors: Shao, Pengcheng P., Ye, Feng, Weber, Ann E., Li, Xiaohua, Lyons, Kathryn A., Parsons, William H., Garcia, Maria L., Priest, Birgit T., Smith, McHardy M., Felix, John P., Williams, Brande S., Kaczorowski, Gregory J., McGowan, Erin, Abbadie, Catherine, Martin, William J., McMasters, Daniel R., Gao, Ying-Duo
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.09.2009; Elsevier
• Subjects: Amide replacement; Analgesics; Animals; Biological and medical sciences; Cell Line; Chronic Disease; Heterocycles; Humans; Inflammatory pain; Isoxazole; Isoxazoles - chemistry; Isoxazoles - pharmacology; Isoxazoles - therapeutic use; Medical sciences; Neuropathic pain; Neuropharmacology; Pain - drug therapy; Pain - immunology; Pharmacology. Drug treatments; Rats; Sodium Channel Blockers - chemistry; Sodium Channel Blockers - pharmacology; Sodium Channel Blockers - therapeutic use; Sodium Channels - metabolism; Spinal Nerves - drug effects; Structure-Activity Relationship; Voltage gated sodium channel blocker; Isoxazole; Heterocycles; Amide replacement; Voltage gated sodium channel blocker; Inflammatory pain; Neuropathic pain; Voltage-gated canal; Isoxazole derivatives; Amides; In vitro; Chronic; Analgesic; Treatment; Structure activity relation; Cyclobutane derivatives; Phenols; Carboxamide; Sodium channel blocker; Fluorine Organic compounds; Chemical synthesis; Cyclopentane derivatives
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.07.135

A series of novel isoxazole voltage gated sodium channel blockers have been synthesized and evaluated. Substitutions on the benzylic position of benzamide were investigated to determine their effect on Na v1.7 inhibitory potency. The spirocyclobutyl substitution had the most significant enhancement on Na v1.7 inhibitory activity.