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

Authors

Capstick RA Rory A , Whomble D David , Orsi DL Douglas L , Felts AS Andrew S , Rodriguez AL Alice L , Vinson PN Paige N , Chang S Sichen , Blobaum AL Anna L , Niswender CM Colleen M , Conn PJ P Jeffrey , Jones CK Carrie K , Lindsley CW Craig W , Han C Changho .
Bioorganic & medicinal chemistry letters. 2022 09 14; 76().
128988

PMID: 36113671

Abstract

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