Discovery of a biarylamide series of potent, state-dependent NaV1.7 inhibitors. Issue 16 (15th August 2017)

• Record Type: Journal Article
• Authors: Schenkel, Laurie B.; DiMauro, Erin F.; Nguyen, Hanh N.; Chakka, Nagasree; Du, Bingfan; Foti, Robert S.; Guzman-Perez, Angel; Jarosh, Michael; La, Daniel S.; Ligutti, Joseph; Milgram, Benjamin C.; Moyer, Bryan D.; Peterson, Emily A.; Roberts, John; Yu, Violeta L.; Weiss, Matthew M.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 27:Issue 16(2017)
• Page Start: 3817
• Page End: 3824
• Publication Date: 2017-08-15
• Subjects: Sodium channel -- NaV1.7 -- NaV1.5 -- State-dependent -- Pain; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2017.06.054
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: The NaV 1.7 ion channel has garnered considerable attention as a target for the treatment of pain. Herein we detail the discovery and structure-activity relationships of a novel series of biaryl amides. Optimization led to the identification of several state-dependent, potent and metabolically stable inhibitors which demonstrated promising levels of selectivity over NaV 1.5 and good rat pharmacokinetics. Compound18, which demonstrated preferential inhibition of a slow inactivated state of NaV 1.7, was advanced into a rat formalin study where upon reaching unbound drug levels several fold over the rat NaV 1.7 IC50 it failed to demonstrate a robust reduction in nociceptive behavior.