2. Academic Validation
  3. Discovery of a biarylamide series of potent, state-dependent NaV1.7 inhibitors

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

Affiliations

  • 1 Department of Therapeutic Discovery, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, United States. Electronic address: mmweiss@amgen.com.
  • 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.

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