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

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.

SUBMITTER: Capstick RA 

PROVIDER: S-EPMC10939060 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Discovery of a potent M<sub>5</sub> antagonist with improved clearance profile. Part 1: Piperidine amide-based antagonists.

Capstick Rory A RA   Whomble David D   Orsi Douglas L DL   Felts Andrew S AS   Rodriguez Alice L AL   Vinson Paige N PN   Chang Sichen S   Blobaum Anna L AL   Niswender Colleen M CM   Conn P Jeffrey PJ   Jones Carrie K CK   Lindsley Craig W CW   Han Changho C  

Bioorganic & medicinal chemistry letters 20220914

The lack of potent and selective tool compounds with pharmaceutically favorable properties limits the in vivo understanding of muscarinic acetylcholine receptor subtype 5 (M<sub>5</sub>) biology. Previously, we presented a highly potent and selective M<sub>5</sub> antagonist VU6019650 with a suboptimal clearance profile as our second-generation tool compound. Herein, we disclose our ongoing efforts to generate next-generation M<sub>5</sub> antagonists with improved clearance profiles. A mix and  ...[more]

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