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

Published on May 20, 2026

ACS Med Chem Lett. 2026 Apr 24;17(5):1189-1194. doi: 10.1021/acsmedchemlett.6c00132. eCollection 2026 May 14.

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.

PMID:42157811 | PMC:PMC13181491 | DOI:10.1021/acsmedchemlett.6c00132

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