Discovery of Indole- and Indazole-acylsulfonamides as Potent and Selective NaV1.7 Inhibitors for the Treatment of Pain

  • J Med Chem. 2019 Jan 24;62(2):831-856. doi: 10.1021/acs.jmedchem.8b01550.
Guanglin Luo  1 ,  Ling Chen  1 ,  Amy Easton  1 ,  Amy Newton  1 ,  Clotilde Bourin  1 ,  Eric Shields  1 ,  Kathy Mosure  1 ,  Matthew G Soars  1 ,  Ronald J Knox  1 ,  Michele Matchett  1 ,  Rick L Pieschl  1 ,  Debra J Post-Munson  1 ,  Shuya Wang  1 ,  James Herrington  1 ,  John Graef  1 ,  Kimberly Newberry  1 ,  Digavalli V Sivarao  1 ,  Arun Senapati  1 ,  Linda J Bristow  1 ,  Nicholas A Meanwell  1 ,  Lorin A Thompson  1 ,  Carolyn Dzierba  1
Affiliations
  • 1. Bristol-Myers Squibb Research and Development , PO Box 4000, Princeton , New Jersey 08543-4000 , United States.
PMID: 30576602 DOI: 10.1021/acs.jmedchem.8b01550
Abstract

3-Aryl-indole and 3-aryl-indazole derivatives were identified as potent and selective Nav1.7 inhibitors. Compound 29 was shown to be efficacious in the mouse formalin assay and also reduced complete Freund's Adjuvant (CFA)-induced thermal hyperalgesia and chronic constriction injury (CCI) induced cold allodynia and models of inflammatory and neuropathic pain, respectively, following intraperitoneal (IP) doses of 30 mg/kg. The observed efficacy could be correlated with the mouse dorsal root ganglion exposure and NaV1.7 potency associated with 29.