Discovery of a novel 2,4-dimethylquinoline-6-carboxamide M4 positive allosteric modulator (PAM) chemotype via scaffold hopping

Madeline F Long; Julie L Engers; Sichen Chang; Xiaoyan Zhan; Rebecca L Weiner; Vincent B Luscombe; Alice L Rodriguez; Hyekyung P Cho; Colleen M Niswender; Thomas M Bridges; P Jeffrey Conn; Darren W Engers; Craig W Lindsley

doi:10.1016/j.bmcl.2017.10.016

Discovery of a novel 2,4-dimethylquinoline-6-carboxamide M₄ positive allosteric modulator (PAM) chemotype via scaffold hopping

Bioorg Med Chem Lett. 2017 Nov 15;27(22):4999-5001. doi: 10.1016/j.bmcl.2017.10.016. Epub 2017 Oct 9.

Affiliations

¹ Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, 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, 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, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. Electronic address: darren.engers@vanderbilt.edu.
⁴ Vanderbilt 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. Electronic address: craig.lindsley@vanderbilt.edu.

Abstract

This Letter details our efforts to replace the 3-amino moiety, an essential pharmacophore for M₄ PAM activity in most M₄ PAMs to date, within the thieno[2,3-b]pyridine core, as the β-amino carboxamide motif has been shown to engender poor solubility, varying degrees of P-gp efflux and represents a structural alert. A scaffold hopping exercise identified a novel 2,4-dimethylquinoline carboxamide core that provided M₄ PAM activity and good CNS penetration without an amino moiety. In addition, MacMillan photoredox catalysis chemistry was essential for construction of the 2,4-dimethylquinoline core.

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

Publication types

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

MeSH terms

Allosteric Regulation
Amides / chemical synthesis
Amides / chemistry*
Amides / pharmacokinetics
Animals
Brain / metabolism
Drug Evaluation, Preclinical
Half-Life
Protein Binding
Pyridines / chemistry
Rats
Rats, Sprague-Dawley
Receptor, Muscarinic M4 / chemistry
Receptor, Muscarinic M4 / metabolism*
Structure-Activity Relationship

Substances

Amides
Pyridines
Receptor, Muscarinic M4
thieno(2,3-b)pyridine