The discovery of benzoxazine sulfonamide inhibitors of NaV1.7: Tools that bridge efficacy and target engagement. Issue 15 (1st August 2017)

• Record Type: Journal Article
• 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.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 27:Issue 15(2017)
• Page Start: 3477
• Page End: 3485
• Publication Date: 2017-08-01
• Subjects: NaV1.7 voltage gated sodium channel 1.7 -- SCN9A sodium voltage-gated channel alpha subunit 9 -- TM transmembrane -- VSD voltage sensing domain -- CLu unbound clearance -- HLM human liver microsome -- RLM rat liver microsome -- PX patch express -- LLE ligand lipophilicity efficiency -- MW molecular weight -- MDCK Madin-Darby canine kidney epithelial -- SAR structure activity relationship -- VDW van der Waals -- MPE maximal pharmacological effect -- CIP congenital insensitivity to pain; Medicinal chemistry -- Nav1.7 -- Pharmacology -- Structure activity relationship; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2017.05.070
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: The voltage-gated sodium channel NaV 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 NaV 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 NaV 1.7 versus human NaV 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 NaV 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.