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：

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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 蛋白内向门控的发现和表征- 整流钾 (GIRK) 通道激活剂。从我们之前的领先优化工作中，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部基团配对，以确定一种有效且具有选择性的 GIRK1/2 激活剂。此外，我们在 1 级 DMPK 测定中评估了化合物，并确定了显示纳摩尔效力的化合物作为 GIRK1/2 激活剂，与基于尿素的原型化合物相比具有更高的代谢稳定性。