Discovery of MK-5661, a Once-Daily Oral NaV1.8 Inhibitor for the Treatment of Pain

  • ACS Med Chem Lett. 2026 Apr 24;17(5):1189-1194. doi: 10.1021/acsmedchemlett.6c00132.
Christopher J Bungard  1 ,  Michael J Breslin  1 ,  Christopher W Boyce  2 ,  Harry R Chobanian  3 ,  Michelle K Clements  4 ,  Stephen M Dalby  5 ,  Juliann Ehrhart  6 ,  ChienJung Huang  4 ,  Kristen G Jones  1 ,  Richard L Kraus  4 ,  Mark E Layton  1 ,  Yuxing Li  4 ,  Maria Madeira  3 ,  James J Perkins  1 ,  Shawn J Stachel  1 ,  Joshua D Vardigan  4 ,  Deping Wang  7 ,  Xiaoping Zhou  4 ,  Vincent P Santarelli  4 ,  Christopher S Burgey  1
Affiliations
  • 1. Discovery Chemistry, Merck & Co., Inc., West Point, Pennsylvania 19486, United States.
  • 2. Discovery Pharmaceutical Sciences, Merck & Co., Inc., West Point, Pennsylvania 19486, United States.
  • 3. Pharmacokinetics, Dynamics, Metabolism and Bioanalysis, Merck & Co., Inc., Rahway, New Jersey 07065, United States.
  • 4. Neuroscience Biology Discovery, Merck & Co., Inc., West Point, Pennsylvania 19486, United States.
  • 5. Discovery Process Chemistry, Merck & Co., Inc., Rahway, New Jersey 07065, United States.
  • 6. Nonclinical Drug Safety, Merck & Co., Inc., West Point, Pennsylvania 19486, United States.
  • 7. Modeling and Informatics, Merck & Co., Inc., West Point, Pennsylvania 19486, United States.
PMID: 42157811 DOI: 10.1021/acsmedchemlett.6c00132
Abstract

NaV1.8 is a key mediator of peripheral nociceptive signaling and an attractive nonopioid target for pain therapeutics. We report the discovery of MK 5661, a potent, selective, and orally bioavailable NaV1.8 inhibitor amenable to once-daily dosing. Optimization of an initial lead, guided by reduction of PXR activation, and dose optimization focusing on half-life and volume ligand efficiency are described. MK-5661 demonstrates a favorable pharmacokinetic profile in preclinical species, as well as efficacy in preclinical models for pain.

Keywords
non-addictive; once-daily dose; oral inhibitor; peripheral nociceptive signaling; treatment of pain.
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