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 |
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| Authors: | Swagat Sharma Krystian A. Kozek Kristopher K. Abney Sushil Kumar Nagsen Gautam Yazen Alnouti C. David Weaver Corey R. Hopkins |
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| Affiliation: | 1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198-6125, USA;2. Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA;3. School of Graduate Studies and Research, Meharry Medical College, Nashville, TN 37208, USA;4. Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA |
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| 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. |
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| Keywords: | GIRK G protein-regulated inwardly-rectifying potassium channel Activator Tetrazole |
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