Novel M4 positive allosteric modulators derived from questioning the role and impact of a presumed intramolecular hydrogen-bonding motif in β-amino carboxamide-harboring ligands

Michael S Poslusney; James M Salovich; Michael R Wood; Bruce J Melancon; Katrina A Bollinger; Vincent B Luscombe; Alice L Rodriguez; Darren W Engers; Thomas M Bridges; Colleen M Niswender; P Jeffrey Conn; Craig W Lindsley

doi:10.1016/j.bmcl.2018.12.039

Novel M₄ positive allosteric modulators derived from questioning the role and impact of a presumed intramolecular hydrogen-bonding motif in β-amino carboxamide-harboring ligands

Bioorg Med Chem Lett. 2019 Feb 1;29(3):362-366. doi: 10.1016/j.bmcl.2018.12.039. Epub 2018 Dec 18.

Affiliations

¹ Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, School of Medicine, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University, School of Medicine, Nashville, TN 37232, USA.
² Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, School of Medicine, 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 Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, School of Medicine, 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; Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: craig.lindsley@vanderbilt.edu.

Abstract

This letter describes a focused exercise to explore the role of the β-amino carboxamide moiety found in all of the first generation M₄ PAMs and question if the NH₂ group served solely to stabilize an intramolecular hydrogen bond (IMHB) and enforce planarity. To address this issue (and to potentially find a substitute for the β-amino carboxamide that engendered P-gp and contributed to solubility liabilities), we removed the NH₂, generating des-amino congeners and surveyed other functional groups in the β-position. These modifications led to weak M₄ PAMs with poor DMPK properties. Cyclization of the β-amino carboxamide moiety by virtue of a pyrazole ring re-enforced the IMHB, led to potent (and patented) M₄ PAMs, many as potent as the classical bicyclic β-amino carboxamide analogs, but with significant CYP1A2 inhibition. Overall, this exercise indicated that the β-amino carboxamide moiety most likely facilitates an IMHB, and is essential for M₄ PAM activity within classical bicyclic M₄ PAM scaffolds.

Keywords: M(4); Muscarinic acetylcholine receptor; Positive allosteric modulator (PAM); Structure-Activity Relationship (SAR); Tricycle.

Publication types

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

MeSH terms

Allosteric Regulation / drug effects
Amides / chemical synthesis
Amides / chemistry
Amides / pharmacology*
Dose-Response Relationship, Drug
Humans
Hydrogen Bonding
Ligands
Molecular Structure
Receptor, Muscarinic M4 / antagonists & inhibitors*
Receptor, Muscarinic M4 / metabolism
Structure-Activity Relationship

Substances

Amides
Ligands
Receptor, Muscarinic M4