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

  • ACS Med Chem Lett. 2026 May 1;17(5):1179-1188. doi: 10.1021/acsmedchemlett.6c00130.
Clemens Dialer  1 ,  Sebastian Krüger  1 ,  Markus Wagener  1 ,  Marcel Mülbaier  1 ,  Sebastian Peil  1 ,  Mauro Marigo  2 ,  Silke Hagendorf  1 ,  Lishuang Cao  3 ,  Cesar Ramirez Molina  3 ,  Paul Morgan  3 ,  Clint Young  4 ,  Lyn Rosenbrier Ribeiro  3 ,  Inna Slynko  1 ,  Stefanie Ritter  1 ,  Monica Guberman  1 ,  Manuela Hass  1 ,  Sascha Klosky  1 ,  Uta la Tendresse  1 ,  Carsten Gussmann  1 ,  Sven Kühnert  1 ,  Stefanie Peters  1 ,  Sara Reichardt-Ockenfeld  1 ,  Hannah Depmeier  1 ,  Florian Jakob  1
Affiliations
  • 1. Drug Discovery Engine, Grünenthal GmbH, Zieglerstr. 6, 52078 Aachen, Germany.
  • 2. Grünenthal Group, HQ, Zieglerstr. 6, 52078 Aachen, Germany.
  • 3. Drug Discovery Engine, Grunenthal Ltd, Saint Cloud Way, Maidenhead, Berkshire SL6 8BN, United Kingdom.
  • 4. Cambridge Innovation Center, GRT Therapeutics, Inc., 11th Floor, 1 Broadway, Cambridge, Massachusetts 02142, United States.
PMID: 42157827 DOI: 10.1021/acsmedchemlett.6c00130
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 (K p,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.

Keywords
NaV1.8 inhibitor; SCN10A; nonopioid analgesics; selective sodium channel blocker; urea.
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