Discovery of a potent M5 antagonist with improved clearance profile. Part 1: Piperidine amide-based antagonists. (15th November 2022)

• Record Type: Journal Article
• Authors: Capstick, Rory A.; Whomble, David; Orsi, Douglas L.; Felts, Andrew S.; Rodriguez, Alice L.; Vinson, Paige N.; Chang, Sichen; Blobaum, Anna L.; Niswender, Colleen M.; Conn, P. Jeffrey; Jones, Carrie K.; Lindsley, Craig W.; Han, Changho
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 76(2022)
• Publication Date: 2022-11-15
• Subjects: Muscarinic acetylcholine receptor 5 -- mAChR -- M5 -- Antagonist; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2022.128988
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: 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.