Discovery of structurally distinct tricyclic M4 positive allosteric modulator (PAM) chemotypes

Kayla J Temple; Madeline F Long; Julie L Engers; Katherine J Watson; Sichen Chang; Vincent B Luscombe; Alice L Rodriguez; Colleen M Niswender; Thomas M Bridges; P Jeffrey Conn; Darren W Engers; Craig W Lindsley

doi:10.1016/j.bmcl.2019.126811

Discovery of structurally distinct tricyclic M₄ positive allosteric modulator (PAM) chemotypes

Bioorg Med Chem Lett. 2020 Feb 15;30(4):126811. doi: 10.1016/j.bmcl.2019.126811. Epub 2019 Nov 11.

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; Vanderbilt Institute of Chemical Biology, Vanderbilt University, 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; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA.

PMID: 31787491
DOI: 10.1016/j.bmcl.2019.126811

Abstract

This Letter details our efforts to develop new M₄ PAM scaffolds with improved pharmacological properties. This endeavor involved replacing the 3,4-dimethylpyridazine core with two novel cores: a 2,3-dimethyl-2H-indazole-5-carboxamide core or a 1-methyl-1H-benzo[d][1,2,3]triazole-6-carboxamide core. Due to shallow SAR, these cores were further evolved into two unique tricyclic cores: an 8,9-dimethyl-8H-pyrazolo[3,4-h]quinazoline core and an 1-methyl-1H-[1,2,3]triazolo[4,5-h]quinazoline core. Both tricyclic cores displayed low nanomolar potency against both human and rat M₄.

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
Animals
Drug Design
Half-Life
Humans
Inhibitory Concentration 50
Pyridazines / chemistry*
Pyridazines / metabolism
Pyridazines / pharmacokinetics
Quinazolines / chemistry*
Quinazolines / metabolism
Quinazolines / pharmacokinetics
Rats
Receptor, Muscarinic M4 / chemistry*
Receptor, Muscarinic M4 / metabolism
Structure-Activity Relationship
Triazoles / chemistry*
Triazoles / metabolism
Triazoles / pharmacokinetics

Substances

Pyridazines
Quinazolines
Receptor, Muscarinic M4
Triazoles
triazoloquinazoline
pyridazine