Discovery of a potent M5 antagonist with improved clearance profile. Part 2: Pyrrolidine amide-based antagonists

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

doi:10.1016/j.bmcl.2022.129021

Discovery of a potent M₅ antagonist with improved clearance profile. Part 2: Pyrrolidine amide-based antagonists

Bioorg Med Chem Lett. 2022 Dec 15:78:129021. doi: 10.1016/j.bmcl.2022.129021. Epub 2022 Oct 10.

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; Vanderbilt Institute of Chemical Biology, Vanderbilt University, 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

This Letter describes our ongoing effort to improve the clearance of selective M₅ antagonists. Herein, we report the replacement of the previously disclosed piperidine amide (4, disclosed in Part 1) with a pyrrolidine amide core. Several compounds within this series provided good potency, subtype selectivity, and low to moderate clearance profiles. Interestingly, the left-hand side SAR for this series diverged from our earlier efforts.

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
Muscarinic Antagonists
Pyrrolidines* / pharmacology

Substances

Amides
Pyrrolidines
Muscarinic Antagonists

Grants and funding

P30 CA068485/CA/NCI NIH HHS/United States