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

doi:10.1039/d1md00129a

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

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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.

Original language	English (US)
Pages (from-to)	1366-1373
Number of pages	8
Journal	RSC Medicinal Chemistry
Volume	12
Issue number	8
DOIs	https://doi.org/10.1039/d1md00129a
State	Published - Aug 2021

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Pharmacology
Pharmaceutical Science
Drug Discovery
Organic Chemistry

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Sharma, S., Lesiak, L., Aretz, C. D., Du, Y., Kumar, S., Gautam, N., Alnouti, Y., Dhuria, N. V., Chhonker, Y. S., Weaver, C. D., & Hopkins, C. R. (2021). 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. RSC Medicinal Chemistry, 12(8), 1366-1373. https://doi.org/10.1039/d1md00129a

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. / Sharma, Swagat; Lesiak, Lauren; Aretz, Christopher D. et al.
In: RSC Medicinal Chemistry, Vol. 12, No. 8, 08.2021, p. 1366-1373.

Research output: Contribution to journal › Article › peer-review

Sharma, S, Lesiak, L, Aretz, CD, Du, Y, Kumar, S, Gautam, N, Alnouti, Y, Dhuria, NV, Chhonker, YS, Weaver, CD & Hopkins, CR 2021, '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', RSC Medicinal Chemistry, vol. 12, no. 8, pp. 1366-1373. https://doi.org/10.1039/d1md00129a

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title = "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",

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.",

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AU - Kumar, Sushil

AU - Gautam, Nagsen

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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

Abstract

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