Discovery and Optimization of Selective Na_v1.8 Modulator Series That Demonstrate Efficacy in Preclinical Models of Pain

Abstract

Voltage-gated sodium channels, in particular Nav1.8, can be targeted for the treatment of neuropathic and inflammatory pain. Herein, we described the optimization of Nav1.8 modulator series to deliver subtype selective, state, and use-dependent chemical matter that is efficacious in preclinical models of neuropathic and inflammatory pain.

Managing Neuropathic Pain in Dogs

“…However, it may persist in scenarios of continued disease or injury, leading to physical alterations in the functions of primary afferent neurons ( 18 ). Sodium channels are considered the primary player in this phenomenon, where increased numbers of heterotopic sodium channels such as Nav1.8, Nav1.7, and Nav1.3 lower stimulus threshold and result in neuropathic pain ( 19 – 22 ).…”

Voltage gated sodium channels as drug discovery targets

“…34 For example, compound 21 has a whole cell electrophysiology Na V 1.8 IC 50 of 260 nM and selectivity of >20-fold over Na V 1.1, Na V 1.5 and Na V 1.7. A collaboration between Abbott and Icagen has also discovered 6,6 and 6,5 biaryl lead matter with an alternative amide geometry.…”

The voltage‐gated sodium channel NaV1.9 in visceral pain

“…This may be particularly relevant for GI disorders, where there is an unmet medical need for mechanistically novel analgesics and where the expression profile of Na V 1.9 within myenteric neurones is favorable for disease‐modifying effects. The development of cell lines heterologously expressing Na V 1.9 that are amenable to small molecule screening techniques alongside the progress of selective potent small molecule inhibitors targeting other sodium channel subtypes, provides a roadmap to the identification of pharmacological inhibitors of Na V 1.9 . Other modalities affecting ion channel function may also be amenable to the modulation of Na V 1.9 function, including blocking antibodies and further work is required to validate such techniques.…”

“…The development of cell lines heterologously expressing Na V 1.9 that are amenable to small molecule screening techniques alongside the progress of selective potent small molecule inhibitors targeting other sodium channel subtypes, provides a roadmap to the identification of pharmacological inhibitors of Na V 1.9. 75,76 Other modalities affecting ion channel function may also be amenable to the modulation of Na V 1.9 function, including blocking antibodies 77 and further work is required to validate such techniques. As such, Na V 1.9 represents a unique modulator of visceral afferent excitability capable of significantly impacting the development of visceral pain.…”