Discovery of a novel 2,3-dimethylimidazo[1,2-a]pyrazine-6-carboxamide M4 positive allosteric modulator (PAM) chemotype

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

doi:10.1016/j.bmcl.2019.126812

Discovery of a novel 2,3-dimethylimidazo[1,2-a]pyrazine-6-carboxamide M₄ positive allosteric modulator (PAM) chemotype

Bioorg Med Chem Lett. 2020 Feb 1;30(3):126812. doi: 10.1016/j.bmcl.2019.126812. Epub 2019 Nov 13.

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: 31784320
DOI: 10.1016/j.bmcl.2019.126812

Abstract

This Letter details our efforts to discover structurally unique M₄ PAMs containing 5,6-heteroaryl ring systems. In an attempt to improve the DMPK profiles of the 2,3-dimethyl-2H-indazole-5-carboxamide and 1-methyl-1H-benzo[d][1,2,3]triazole-6-carboxamide cores, we investigated a plethora of core replacements. This exercise identified a novel 2,3-dimethylimidazo[1,2-a]pyrazine-6-carboxamide core that provided improved M₄ PAM activity and CNS penetration.

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
Drug Design
Drug Evaluation, Preclinical
Humans
Imidazoles / chemistry*
Imidazoles / metabolism
Kinetics
Protein Binding
Pyrazines / chemistry*
Pyrazines / metabolism
Receptor, Muscarinic M4 / chemistry*
Receptor, Muscarinic M4 / metabolism
Structure-Activity Relationship

Substances

Imidazoles
Pyrazines
Receptor, Muscarinic M4
imidazo(1,5-a)pyrazine