Discovery of a novel 3,4-dimethylcinnoline carboxamide M positive allosteric modulator (PAM) chemotype via scaffold hopping.

Temple KJ, Engers JL, Long MF, Gregro AR, Watson KJ, Chang S, Jenkins MT, Luscombe VB, Rodriguez AL, Niswender CM, Bridges TM, Conn PJ, Engers DW, Lindsley CW
Bioorg Med Chem Lett. 2019 29 (21): 126678

PMID: 31537424 · DOI:10.1016/j.bmcl.2019.126678

This Letter details our efforts to replace the 2,4-dimethylquinoline carboxamide core of our previous M PAM series, which suffered from high predicted hepatic clearance and protein binding. A scaffold hopping exercise identified a novel 3,4-dimethylcinnoline carboxamide core that provided good M PAM activity and improved clearance and protein binding profiles.

Copyright © 2019 Elsevier Ltd. All rights reserved.

MeSH Terms (11)

Allosteric Regulation Amides Azetidines Benzene Molecular Structure Protein Binding Pyrazines Pyridines Pyrimidines Receptor, Muscarinic M4 Structure-Activity Relationship

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