Discovery of a potent M5 antagonist with improved clearance profile. Part 1: Piperidine amide-based antagonists

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.

Automated summary

The lack of suitable tool compounds has restricted the in vivo understanding of M5 receptor biology. In this article, the authors present their ongoing efforts to develop next-generation M5 antagonists with improved clearance profiles.