Discovery of MK-5661, a Once-Daily Oral Na V 1.8 Inhibitor for the Treatment of Pain

ACS Medicinal Chemistry Letters 2026 Open access

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Authors: Christopher J. Bungard, Michael J. Breslin, Christopher W. Boyce, Harry R. Chobanian, Michelle K. Clements, Stephen M. Dalby, Juliann Ehrhart, Huang ChienJung, Kristen G. Jones, Richard L. Kraus, Mark E. Layton, Yuxing Li
+8 more Maria Madeira, James J. Perkins, Shawn J. Stachel, Joshua D. Vardigan, D Z Wang, Xiaoping Zhou, Vincent P. Santarelli, Christopher S. Burgey
DOI: 10.1021/acsmedchemlett.6c00132
Cited by: 1
References: 21

Abstract

Na V 1.8 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 Na V 1.8 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.

Fields of Study & Subjects

Ion Transport and Channel Regulation Ion channel regulation and function Magnesium in Health and Disease

Publication details

Journal / source
ACS Medicinal Chemistry Letters
Publisher
American Chemical Society (ACS)
Volume
17
Issue
5
Pages
1189–1194
Publication date
24 April 2026
Language
EN