Issue 8, 2021

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

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.

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

Supplementary files

Article information

Article type
Research Article
Submitted
15 apr 2021
Accepted
04 jun 2021
First published
21 jun 2021

RSC Med. Chem., 2021,12, 1366-1373

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

S. Sharma, L. Lesiak, C. D. Aretz, Y. Du, S. Kumar, N. Gautam, Y. Alnouti, N. V. Dhuria, Y. S. Chhonker, C. D. Weaver and C. R. Hopkins, RSC Med. Chem., 2021, 12, 1366 DOI: 10.1039/D1MD00129A

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