2-Aminopyridines as Potent and Selective Na v 1.8 Inhibitors Exhibiting Efficacy in a Nonhuman Primate Pain Model.

Autor: Breslin MJ; Discovery Chemistry, Merck & Co., Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486, United States., Schubert JW; Discovery Chemistry, Merck & Co., Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486, United States., Wang D; Modeling and Informatics, Merck & Co., Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486, United States., Huang C; Neuroscience Biology Discovery, Merck & Co., Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486, United States., Clements MK; Neuroscience Biology Discovery, Merck & Co., Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486, United States., Li Y; Neuroscience Biology Discovery, Merck & Co., Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486, United States., Zhou X; Neuroscience Biology Discovery, Merck & Co., Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486, United States., Vardigan JD; Neuroscience Biology Discovery, Merck & Co., Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486, United States., Kraus RL; Neuroscience Biology Discovery, Merck & Co., Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486, United States., Santarelli VP; Neuroscience Biology Discovery, Merck & Co., Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486, United States., Uslaner JM; Preclinical and Translational Medicine Discovery, Merck & Co., Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486, United States., Coleman PJ; Discovery Chemistry, Merck & Co., Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486, United States., Stachel SJ; Discovery Chemistry, Merck & Co., Inc., 770 Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486, United States.
Jazyk: angličtina
Zdroj: ACS medicinal chemistry letters [ACS Med Chem Lett] 2024 May 24; Vol. 15 (6), pp. 917-923. Date of Electronic Publication: 2024 May 24 (Print Publication: 2024).
DOI: 10.1021/acsmedchemlett.4c00103
Abstrakt: Herein we describe the discovery of a 2-aminopyridine scaffold as a potent and isoform selective inhibitor of the Na v 1.8 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.
Competing Interests: The authors declare no competing financial interest.
(© 2024 American Chemical Society.)
Databáze: MEDLINE
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