We sought to develop RORβ-selective probe molecules in order to investigate the function of the receptor in vitro and in vivo and its role in the pathophysiology of disease. To accomplish this, we modified a potent dual RORβ/RORγ inverse agonist from the primary literature with the goal of improving selectivity for RORβ vs RORγ. Truncation of the Western portion of the molecule ablated activity at RORγ and led to a potent series of RORβ modulators. Continued exploration of this series investigated alternate replacement cores for the aminothiazole ring. Numerous suitable replacements were found during the course of our SAR investigations and are reported herein.

我们试图开发 RORβ 选择性探针分子，以研究受体在体外和体内的功能及其在疾病病理生理学中的作用。为实现这一目标，我们从主要文献中修改了一种有效的双重 RORβ/RORγ 反向激动剂，目的是提高 RORβ 与 RORγ 的选择性。分子西部部分的截断消除了 RORγ 的活性，并产生了一系列有效的 RORβ 调节剂。该系列的继续探索研究了氨基噻唑环的替代替代核心。在我们的 SAR 调查过程中发现了许多合适的替代品，并在此处报告。