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,RSC Medicinal Chemistry

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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
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2021-6-21 , DOI: 10.1039/d1md00129a
Swagat Sharma ₁ , Lauren Lesiak ₁ , Christopher D Aretz ₁ , Yu Du ₂ , Sushil Kumar ₁ , Nagsen Gautam ₁ , Yazen Alnouti ₁ , Nikilesh V Dhuria ₃ , Yashpal S Chhonker ₃ , C David Weaver ₂ , Corey R Hopkins ₁

Affiliation

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.

中文翻译：

一系列 N-(1-(1,1-二氧化四氢噻吩-3-基)-3-甲基-1H-吡唑-5-基)乙酰胺醚作为新型 GIRK1/2 钾通道激活剂的发现、合成和生物学表征

本研究描述了一系列N -(1-(1,1-二氧化四氢噻吩-3-基)-3-甲基-1 H-吡唑-5-基)乙酰胺醚作为 G 蛋白内门控的发现和表征-整流钾（GIRK）通道激活剂。从我们之前的先导化合物优化工作中，我们已经确定了一种新的基于醚的支架，并将其与一种新型的基于砜的头基配对，以确定一种有效且选择性的 GIRK1/2 激活剂。此外，我们在第 1 层 DMPK 测定中评估了这些化合物，并确定了作为 GIRK1/2 激活剂显示纳摩尔效力的化合物，与典型的基于尿素的化合物相比，其代谢稳定性得到了改善。

更新日期：2021-06-21

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