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

被引：0

作者：

Sharma, Swagat ^{[1
]}

Lesiak, Lauren ^{[1
]}

Aretz, Christopher D. ^{[1
]}

Du, Yu ^{[2
]}

Kumar, Sushil ^{[1
]}

Gautam, Nagsen ^{[1
]}

Alnouti, Yazen ^{[1
]}

Dhuria, Nikilesh, V ^{[3
]}

Chhonker, Yashpal S. ^{[3
]}

Weaver, C. David ^{[2
]}

Hopkins, Corey R. ^{[1
]}

机构：

[1] Univ Nebraska Med Ctr, Coll Pharm, Dept Pharmaceut Sci, Omaha, NE 68198 USA

[2] Vanderbilt Univ, Dept Pharmacol, Sch Med, Nashville, NV 37232 USA

[3] Univ Nebraska Med Ctr, Coll Pharm, Dept Pharm Practice & Sci, Omaha, NE 68198 USA

来源：

RSC MEDICINAL CHEMISTRY | 2021年 / 12卷 / 08期

关键词：

RECTIFYING K+-CHANNEL; MOLECULAR SWITCHES; PROTEIN; DRUG; BINDING; EXPRESSION; CLEARANCE; INSIGHTS; NEURONS; POTENT;

D O I：

10.1039/d1md00129a

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 inwardlyrectifying 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.

引用

页码：1366 / 1373

页数：8

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