The lack of potent and selective tool compounds with pharmaceutically favorable properties limits the in vivo understanding of muscarinic acetylcholine receptor subtype 5 (M₅) biology. Previously, we presented a highly potent and selective M₅ antagonist VU6019650 with a suboptimal clearance profile as our second-generation tool compound. Herein, we disclose our ongoing efforts to generate next-generation M₅ antagonists with improved clearance profiles. A mix and match approach between VU6019650 (lead) and VU0500325 (HTS hit) generated a piperidine amide-based novel M₅ antagonist series. Several analogs within this series, including 29f, provided good on-target potency with improved clearance profiles, though room for improvement remains.

缺乏具有药学上有利特性的有效和选择性工具化合物限制了对毒蕈碱乙酰胆碱受体亚型 5 (M ₅ ) 生物学的体内理解。此前，我们提出了一种高效、选择性的 M ₅拮抗剂 VU6019650，其清除率不理想，作为我们的第二代工具化合物。在此，我们披露了我们为产生具有改进的清除特性的下一代 M ₅拮抗剂所做的持续努力。 VU6019650（先导）和 VU0500325（HTS 热门）之间的混合搭配方法产生了基于哌啶酰胺的新型 M ₅拮抗剂系列。该系列中的几种类似物，包括29f ，提供了良好的靶向效力，并改善了间隙分布，但仍有改进的空间。