2. Academic Validation
  3. Discovery and Optimization of Potent and Subtype-Selective Urea-Derived NaV1.8 Inhibitors

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

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.

Figures
Products