Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University , Nashville, Tennessee 37232, United States.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center , Omaha, Nebraska 68198, United States.
ACS Chem Neurosci. 2017 Sep 20;8(9):1873-1879. doi: 10.1021/acschemneuro.7b00217. Epub 2017 Jul 19.
The G protein-gated inwardly-rectifying potassium channels (GIRK, K3) are a family of inward-rectifying potassium channels, and there is significant evidence supporting the roles of GIRKs in a number of physiological processes and as potential targets for numerous indications. Previously reported urea containing molecules as GIRK1/2 preferring activators have had significant pharmacokinetic (PK) liabilities. Here we report a novel series of 1H-pyrazolo-5-yl-2-phenylacetamides in an effort to improve upon the PK properties. This series of compounds display nanomolar potency as GIRK1/2 activators with improved brain distribution (rodent K > 0.6).
G 蛋白门控内向整流钾通道（GIRK，K3）是内向整流钾通道家族的一员，有大量证据表明它们在许多生理过程中发挥作用，并可能成为许多适应症的潜在靶点。以前报道的含脲分子作为 GIRK1/2 的优先激活剂具有显著的药代动力学（PK）缺陷。在这里，我们报告了一系列新型的 1H-吡唑并-5-基-2-苯基乙酰胺，旨在改善 PK 性质。该系列化合物作为 GIRK1/2 激活剂具有纳摩尔效力，并且改善了脑分布（啮齿动物 K > 0.6）。
