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

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; M. E. Layton; Yuxing Li; 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

Key Points

This research aims to develop a selective NaV1.8 inhibitor for effective pain treatment without opioids.
Optimization of an initial lead compound focusing on reduced PXR activation.
Development of a dosing regimen aimed at enhancing half-life and ligand efficiency.
In vivo assessment of pharmacokinetic properties and efficacy in preclinical pain models.
MK-5661 is a potent and selective NaV1.8 inhibitor with a favorable pharmacokinetic profile.
Demonstrated significant efficacy in preclinical models for pain relief.
Indicates potential for once-daily oral dosing.

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Implication

Study discovers MK-5661's effectiveness in managing pain, suggesting new nonopioid therapy options.

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.

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Bungard et al. (2026) studied this question.

synapsesocial.com/papers/69eefcaefede9185760d389a https://doi.org/10.1021/acsmedchemlett.6c00132

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

Key Points

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Implication

Abstract

Discussion

Cite This Study

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

Key Points

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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