Discovery of a biarylamide series of potent, state-dependent NaV1.7 inhibitors

  • Bioorg Med Chem Lett. 2017 Aug 15;27(16):3817-3824. doi: 10.1016/j.bmcl.2017.06.054.
Laurie B Schenkel  1 ,  Erin F DiMauro  2 ,  Hanh N Nguyen  2 ,  Nagasree Chakka  2 ,  Bingfan Du  2 ,  Robert S Foti  3 ,  Angel Guzman-Perez  2 ,  Michael Jarosh  4 ,  Daniel S La  2 ,  Joseph Ligutti  5 ,  Benjamin C Milgram  2 ,  Bryan D Moyer  5 ,  Emily A Peterson  2 ,  John Roberts  3 ,  Violeta L Yu  4 ,  Matthew M Weiss  2
Affiliations
  • 1. Department of Therapeutic Discovery, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, United States. Electronic address: [email protected].
  • 2. Department of Therapeutic Discovery, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, United States.
  • 3. Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, United States.
  • 4. Department of Neuroscience, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, United States.
  • 5. Department of Neuroscience, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States.
PMID: 28684121 DOI: 10.1016/j.bmcl.2017.06.054
Abstract

The NaV1.7 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 NaV1.5 and good rat pharmacokinetics. Compound 18, which demonstrated preferential inhibition of a slow inactivated state of NaV1.7, was advanced into a rat formalin study where upon reaching unbound drug levels several fold over the rat NaV1.7 IC50 it failed to demonstrate a robust reduction in nociceptive behavior.

Keywords
Na(V)1.5; Na(V)1.7; Pain; Sodium channel; State-dependent.