Synthesis and SAR of substituted pyrazolo[1,5-a]quinazolines as dual mGlu(2)/mGlu(3) NAMs.

Wenthur CJ, Morrison RD, Daniels JS, Conn PJ, Lindsley CW
Bioorg Med Chem Lett. 2014 24 (12): 2693-8

PMID: 24794112 · PMCID: PMC4075068 · DOI:10.1016/j.bmcl.2014.04.051

Herein we report the design and synthesis of a series of substituted pyrazolo[1,5-a]quinazolin-5(4H)-ones as negative allosteric modulators of metabotropic glutamate receptors 2 and 3 (mGlu2 and mGlu3, respectively). Development of this series was initiated by reports that pyrazolo[1,5-a]quinazoline-derived scaffolds can yield compounds with activity at group II mGlu receptors which are prone to molecular switching following small structural changes. Several potent analogues, including 4-methyl-2-phenyl-8-(pyrimidin-5-yl)pyrazolo[1,5-a]quinazolin-5(4H)-one (10b), were discovered with potent in vitro activity as dual mGlu2/mGlu3 NAMs, with excellent selectivity versus the other mGluRs.

Copyright © 2014 Elsevier Ltd. All rights reserved.

MeSH Terms (8)

Allosteric Regulation Drug Design Inhibitory Concentration 50 Molecular Structure Pyrazoles Quinazolines Receptors, Metabotropic Glutamate Structure-Activity Relationship

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