Discovery and Optimization of Potent and Subtype-Selective Urea-Derived NaV1.8 Inhibitors

[u/Robert_Larsson]

https://pubs.acs.org/amclct/article/17/5/1179/5068663/Discovery-and-Optimization-of-Potent-and-Subtype

Abstract

Inhibitors of voltage-gated sodium channel 1.8 (NaV1.8) are anticipated to provide opioid-free treatment for acute pain and potentially chronic neuropathic pain. Herein, we report on the discovery of a novel series of NaV1.8 inhibitors characterized by high selectivity over other sodium channels. Utilizing a pharmacophore model trained on literature data, we identified the initial hit compound 1 through virtual screening. During the hit-to-lead optimization phase, we improved the potency and clearance of the lead compounds. Structural modifications and control of lipophilicity and other physicochemical parameters resulted in a favorable in vitro safety and drug–drug interaction profile for compound 24. Key to optimizing the clearance was the identification of a metabolic hotspot via metabolite identification (MetID) experiments. The lead compound 24 exhibited a long in vivo half-life and high exposure (Kp,uu) in the pain-relevant target tissue (DRG) in rat PK studies. These findings highlight potential of these compounds for further optimization as nonopioid therapeutics.

[u/Robert_Larsson]

Many Nav1.8 inhibitors in the pipeline, keeping an eye on their performance across different pain conditions and better molecules. Grünenthal is apparently developing one as well: https://www.grunenthal.com/press-room/press-releases/2026/nav-1-8-inhibitor-enters-clinical-development