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

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.
Rory A Capstick 1,  David Whomble 1,  Douglas L Orsi 1,  Andrew S Felts 1,  Alice L Rodriguez 1,  Paige N Vinson 1,  Sichen Chang 1,  Anna L Blobaum 1,  Colleen M Niswender 2,  P Jeffrey Conn 2,  Carrie K Jones 1,  Craig W Lindsley 3,  Changho Han 4
Affiliations

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.
PMID: 36113671 DOI: 10.1016/j.bmcl.2022.128988
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.

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