Compound 8a (BMS-191011), an opener of the cloned large-conductance, Ca2+-activated potassium (maxi-K) channel, demonstrated efficacy in in vivo stroke models, which led to its nomination as a candidate for clinical evaluation. Its maxi-K channel opening properties were consistent with its structural topology, being derived by combining elements from other known maxi-K openers. However, 8a suffered from poor aqueous solubility, which complicated elucidation of SAR during in vitro evaluation. The activity of 8a in in vivo stroke models and studies directed toward improving its solubility are reported herein. Enhanced solubility was achieved by appending heterocycles to the 8a scaffold, and a notable observation was made that inclusion of a simple amino group (anilines 8k and 8l) yielded excellent in vitro maxi-K ion channel opening activity and enhanced brain-to-plasma partitioning compared to the appended heterocycles.

中文翻译：

---

3-[（5-氯-2-羟基苯基）甲基] -5- [4-（三氟甲基）苯基] -1,3,4-恶二唑-2（3H）-one，BMS-191011：大电导率的开启剂Ca（2+）激活钾（maxi-K）通道，标识，溶解度和SAR。

化合物8a（BMS-191011）是克隆的大电导，Ca2 +激活的钾（maxi-K）通道的开启剂，在体内中风模型中显示出功效，因此被提名为临床评估的候选者。它的maxi-K通道开放特性与它的结构拓扑一致，是通过组合其他已知的maxi-K开孔器中的元素得出的。但是，8a的水溶性差，这使得在体外评估过程中对SAR的阐明变得复杂。本文报道了8a在体内中风模型中的活性以及旨在改善其溶解度的研究。通过将杂环附加到8a支架上来提高溶解度，