Discovery, synthesis and characterization of a series of (1-alkyl-3-methyl-1H-pyrazol-5-yl)-2-(5-aryl-2H-tetrazol-2-yl)acetamides as novel GIRK1/2 potassium channel activators

Swagat Sharma, Krystian A. Kozek, Kristopher K. Abney, Sushil Kumar, Nagsen Gautam, Yazen Alnouti, C. David Weaver, Corey R. Hopkins

Research output: Contribution to journalArticle

Abstract

The present study describes the discovery and characterization of a series of 5-aryl-2H-tetrazol-3-ylacetamides as G protein-gated inwardly-rectifying potassium (GIRK) channels activators. Working from an initial hit discovered during a high-throughput screening campaign, we identified a tetrazole scaffold that shifts away from the previously reported urea-based scaffolds while remaining effective GIRK1/2 channel activators. In addition, we evaluated the compounds in Tier 1 DMPK assays and have identified a (3-methyl-1H-pyrazol-1-yl)tetrahydrothiophene-1,1-dioxide head group that imparts interesting and unexpected microsomal stability compared to previously-reported pyrazole head groups.

Original languageEnglish (US)
Pages (from-to)791-796
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume29
Issue number6
DOIs
StatePublished - Mar 15 2019

Fingerprint

G Protein-Coupled Inwardly-Rectifying Potassium Channels
Acetamides
Inwardly Rectifying Potassium Channel
Potassium Channels
GTP-Binding Proteins
Scaffolds
Urea
Head
Assays
Screening
Throughput
1H-tetrazole
pyrazole
sulfolane

Keywords

  • Activator
  • G protein-regulated inwardly-rectifying potassium channel
  • GIRK
  • Tetrazole

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Discovery, synthesis and characterization of a series of (1-alkyl-3-methyl-1H-pyrazol-5-yl)-2-(5-aryl-2H-tetrazol-2-yl)acetamides as novel GIRK1/2 potassium channel activators. / Sharma, Swagat; Kozek, Krystian A.; Abney, Kristopher K.; Kumar, Sushil; Gautam, Nagsen; Alnouti, Yazen; David Weaver, C.; Hopkins, Corey R.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 29, No. 6, 15.03.2019, p. 791-796.

Research output: Contribution to journalArticle

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