Discovery, synthesis and biological characterization of a series of: N -(1-(1,1-dioxidotetrahydrothiophen-3-yl)-3-methyl-1 H -pyrazol-5-yl)acetamide ethers as novel GIRK1/2 potassium channel activators

Swagat Sharma, Lauren Lesiak, Christopher D. Aretz, Yu Du, Sushil Kumar, Nagsen Gautam, Yazen Alnouti, Nikilesh V. Dhuria, Yashpal S. Chhonker, C. David Weaver, Corey R. Hopkins

Research output: Contribution to journalArticlepeer-review

Abstract

The present study describes the discovery and characterization of a series of N-(1-(1,1-dioxidotetrahydrothiophen-3-yl)-3-methyl-1H-pyrazol-5-yl)acetamide ethers as G protein-gated inwardly-rectifying potassium (GIRK) channel activators. From our previous lead optimization efforts, we have identified a new ether-based scaffold and paired this with a novel sulfone-based head group to identify a potent and selective GIRK1/2 activator. In addition, we evaluated the compounds in tier 1 DMPK assays and have identified compounds that display nanomolar potency as GIRK1/2 activators with improved metabolic stability over the prototypical urea-based compounds. This journal is

Original languageEnglish (US)
Pages (from-to)1366-1373
Number of pages8
JournalRSC Medicinal Chemistry
Volume12
Issue number8
DOIs
StatePublished - Aug 2021

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry

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