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

Rory A Capstick; David Whomble; Douglas L Orsi; Andrew S Felts; Alice L Rodriguez; Paige N Vinson; Sichen Chang; Anna L Blobaum; Colleen M Niswender; P Jeffrey Conn; Carrie K Jones; Craig W Lindsley; Changho Han

doi:10.1016/j.bmcl.2022.128988

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

Bioorg Med Chem Lett. 2022 Nov 15:76:128988. doi: 10.1016/j.bmcl.2022.128988. Epub 2022 Sep 14.

Affiliations

¹ Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
² Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
³ Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: craig.lindsley@vanderbilt.edu.
⁴ Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. Electronic address: changho.han@vanderbilt.edu.

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.

Keywords: Antagonist; M(5); Muscarinic acetylcholine receptor 5; mAChR.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Amides* / pharmacology
Kinetics
Piperidines / pharmacology
Receptors, Muscarinic*

Substances

Amides
Piperidines
Receptors, Muscarinic
VU6019650

Grants and funding

P30 CA068485/CA/NCI NIH HHS/United States