2-Aminopyridines as Potent and Selective Nav1.8 Inhibitors Exhibiting Efficacy in a Nonhuman Primate Pain Model

  • ACS Med Chem Lett. 2024 May 24;15(6):917-923. doi: 10.1021/acsmedchemlett.4c00103.
Michael J Breslin  1 ,  Jeffrey W Schubert  1 ,  Deping Wang  2 ,  Chienjung Huang  3 ,  Michelle K Clements  3 ,  Yuxing Li  3 ,  Xiaoping Zhou  3 ,  Joshua D Vardigan  3 ,  Richard L Kraus  3 ,  Vincent P Santarelli  3 ,  Jason M Uslaner  4 ,  Paul J Coleman  1 ,  Shawn J Stachel  1
Affiliations
  • 1. Discovery Chemistry, Merck & Co., Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486, United States.
  • 2. Modeling and Informatics, Merck & Co., Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486, United States.
  • 3. Neuroscience Biology Discovery, Merck & Co., Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486, United States.
  • 4. Preclinical and Translational Medicine Discovery, Merck & Co., Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486, United States.
PMID: 38894930 DOI: 10.1021/acsmedchemlett.4c00103
Abstract

Herein we describe the discovery of a 2-aminopyridine scaffold as a potent and isoform selective inhibitor of the Nav1.8 Sodium Channel. Parallel library synthesis, guided by in silico predictions, rapidly transformed initial hits into a novel 2-aminopyridine lead class possessing good ADME and pharmacokinetic profiles that were able to display activity in a clinically translatable nonhuman primate capsaicin-sensitized thermode pharmacodynamic assay. Progress toward the lead identification, optimization, and in vivo efficacy of these compounds will be discussed.

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