Discovery of pyridyl urea sulfonamide inhibitors of NaV1.7. (1st October 2022)

• Record Type: Journal Article
• Authors: Butler, John R.; Rescourio, Gwenaella; Milgram, Benjamin C.; Foti, Robert S.; Kornecook, Thomas; Ligutti, Joseph; Moyer, Bryan D.; Taborn, Kristin; Youngblood, Beth D.; Yu, Violeta; Shimanovich, Roman; Boezio, Alessandro; Weiss, Matthew
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 73(2022)
• Publication Date: 2022-10-01
• Subjects: Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2022.128892
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: NaV 1.7 is an actively pursued, genetically validated, target for pain. Recently reported quinolinone sulfonamide inhibitors displayed promising selectivity profiles as well as efficacy in preclinical pain models; however, concerns about off-target liabilities associated with this series resulted in an effort to reduce the lipophilicity of these compounds. Successful prosecution of this strategy was challenging due to the opposing requirement for lipophilic inhibitors for NaV 1.7 potency and in vivo clearance (CL). Deconstruction of the heterocyclic core of the quinolinone series and utilization of an intramolecular hydrogen bond to mimic the requisite pharmacophore enabled the introduction of polarity without adversely impacting CL. Ultimately, this strategy led to the identification of compound 29, which demonstrated favorable ADME and was efficacious in pre-clinical models of pain.