Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198-6125, USA.
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA.
Bioorg Med Chem Lett. 2019 Mar 15;29(6):791-796. doi: 10.1016/j.bmcl.2019.01.027. Epub 2019 Jan 23.
The present study describes the discovery and characterization of a series of 5-aryl-2H-tetrazol-3-ylacetamides as G protein-gated inwardly-rectifying potassium (GIRK) channels activators. Working from an initial hit discovered during a high-throughput screening campaign, we identified a tetrazole scaffold that shifts away from the previously reported urea-based scaffolds while remaining effective GIRK1/2 channel activators. In addition, we evaluated the compounds in Tier 1 DMPK assays and have identified a (3-methyl-1H-pyrazol-1-yl)tetrahydrothiophene-1,1-dioxide head group that imparts interesting and unexpected microsomal stability compared to previously-reported pyrazole head groups.
本研究描述了一系列 5-芳基-2H-四唑-3-基乙酰胺作为 G 蛋白门控内向整流钾 (GIRK) 通道激活剂的发现和特性。从高通量筛选活动中发现的初始命中物开始，我们确定了一个四唑支架，该支架偏离了先前报道的基于脲的支架，同时仍然是有效的 GIRK1/2 通道激活剂。此外，我们还在 DMPK 测试的第 1 层评估了这些化合物，并确定了一个（3-甲基-1H-吡唑-1-基）四氢噻吩-1,1-二氧化物头基团，与先前报道的吡唑头基团相比，它赋予了有趣且出人意料的微粒体稳定性。
