REV-ERBα 的优化化学探针。
Optimized chemical probes for REV-ERBα.
机构信息
Molecular Discovery Research, GlaxoSmithKline, Research Triangle Park, North Carolina 27709-3398, USA.
出版信息
J Med Chem. 2013 Jun 13;56(11):4729-37. doi: 10.1021/jm400458q. Epub 2013 May 23.
Abstract
REV-ERBα has emerged as an important target for regulation of circadian rhythm and its associated physiology. Herein, we report on the optimization of a series of REV-ERBα agonists based on GSK4112 (1) for potency, selectivity, and bioavailability. (1) Potent REV-ERBα agonists 4, 10, 16, and 23 are detailed for their ability to suppress BMAL and IL-6 expression from human cells while also demonstrating excellent selectivity over LXRα. Amine 4 demonstrated in vivo bioavailability after either iv or oral dosing.
摘要
REV-ERBα 已成为调节生物钟及其相关生理机能的重要靶点。在此，我们报告了一系列基于 GSK4112（1）的 REV-ERBα 激动剂的优化，以提高其效力、选择性和生物利用度。（1）详细介绍了强效的 REV-ERBα 激动剂 4、10、16 和 23，它们能够抑制人细胞中的 BMAL 和 IL-6 表达，并且对 LXRα 具有优异的选择性。在静脉注射或口服给药后，胺 4 表现出体内生物利用度。
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