The discovery of benzoxazine sulfonamide inhibitors of Na V 1.7: Tools that bridge efficacy and target engagement

• Published in: Bioorganic & medicinal chemistry letters Vol. 27; no. 15; pp. 3477 - 3485
• Main Authors: La, Daniel S., Peterson, Emily A., Bode, Christiane, Boezio, Alessandro A., Bregman, Howard, Chu-Moyer, Margaret Y., Coats, James, DiMauro, Erin F., Dineen, Thomas A., Du, Bingfan, Gao, Hua, Graceffa, Russell, Gunaydin, Hakan, Guzman-Perez, Angel, Fremeau, Robert, Huang, Xin, Ilch, Christopher, Kornecook, Thomas J., Kreiman, Charles, Ligutti, Joseph, Jasmine Lin, Min-Hwa, McDermott, Jeff S., Marx, Isaac, Matson, David J., McDonough, Stefan I., Moyer, Bryan D., Nho Nguyen, Hanh, Taborn, Kristin, Yu, Violeta, Weiss, Matthew M.
• Format: Journal Article
• Language: English
• Published: England 01.08.2017
• Subjects: Analgesics - chemistry; Analgesics - pharmacokinetics; Analgesics - pharmacology; Analgesics - therapeutic use; Animals; Benzoxazines - chemistry; Benzoxazines - pharmacokinetics; Benzoxazines - pharmacology; Benzoxazines - therapeutic use; Humans; Male; Mice; Mice, Inbred C57BL; Molecular Docking Simulation; NAV1.7 Voltage-Gated Sodium Channel - metabolism; Pain - drug therapy; Pain - metabolism; Rats; Rats, Sprague-Dawley; Sulfonamides - chemistry; Sulfonamides - pharmacokinetics; Sulfonamides - pharmacology; Sulfonamides - therapeutic use; Voltage-Gated Sodium Channel Blockers - chemistry; Voltage-Gated Sodium Channel Blockers - pharmacokinetics; Voltage-Gated Sodium Channel Blockers - pharmacology; Voltage-Gated Sodium Channel Blockers - therapeutic use; Nav1.7; Medicinal chemistry; Structure activity relationship; Pharmacology
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2017.05.070

The voltage-gated sodium channel Na 1.7 has received much attention from the scientific community due to compelling human genetic data linking gain- and loss-of-function mutations to pain phenotypes. Despite this genetic validation of Na 1.7 as a target for pain, high quality pharmacological tools facilitate further understanding of target biology, establishment of target coverage requirements and subsequent progression into the clinic. Within the sulfonamide class of inhibitors, reduced potency on rat Na 1.7 versus human Na 1.7 was observed, rendering in vivo rat pharmacology studies challenging. Herein, we report the discovery and optimization of novel benzoxazine sulfonamide inhibitors of human, rat and mouse Na 1.7 which enabled pharmacological assessment in traditional behavioral rodent models of pain and in turn, established a connection between formalin-induced pain and histamine-induced pruritus in mice. The latter represents a simple and efficient means of measuring target engagement.