Open AccessDiscovery, 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
Author(s) -
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
Publication year - 2021
Publication title -
rsc medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.754
H-Index - 55
ISSN - 2632-8682
DOI - 10.1039/d1md00129a
Subject(s) - acetamide , sulfone , ether , potency , chemistry , activator (genetics) , in vitro , biological activity , combinatorial chemistry , stereochemistry , organic chemistry , biochemistry , receptor
The present study describes the discovery and characterization of a series of N -(1-(1,1-dioxidotetrahydrothiophen-3-yl)-3-methyl-1 H -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.