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

Autor: Stefan I. McDonough, Min-Hwa Jasmine Lin, Erin F. DiMauro, Violeta Yu, Angel Guzman-Perez, Kristin Taborn, Christiane Bode, Thomas Kornecook, Thomas Dineen, Xin Huang, Robert T. Fremeau, Margaret Chu-Moyer, James R. Coats, Bingfan Du, Jeff S. McDermott, Hakan Gunaydin, Daniel S. La, Hua Gao, Bryan D. Moyer, Russell Graceffa, Alessandro Boezio, Charles Kreiman, Matthew Weiss, Hanh Nho Nguyen, David J. Matson, Joseph Ligutti, Christopher P Ilch, Isaac E. Marx, Emily A. Peterson, Howard Bregman
Rok vydání: 2017
Předmět:
Zdroj: Bioorganic & Medicinal Chemistry Letters. 27:3477-3485
ISSN: 0960-894X
Popis: The voltage-gated sodium channel NaV1.7 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 NaV1.7 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 NaV1.7 versus human NaV1.7 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 NaV1.7 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.
Databáze: OpenAIRE
Externí odkaz: