Synthesis and SAR of substituted pyrazolo[1,5-a]quinazolines as dual mGlu2/mGlu3 NAMs

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:24

Article

Wenthur, Cody J.^1,2  Morrison, Ryan D.^1,2  Daniels, J. Scott^1,2  Conn, P. Jeffrey^1,2  Lindsley, Craig W.^1,2,3 

[1] Vanderbilt Univ, Med Ctr, Dept Pharmacol, Nashville, TN 37232 USA

[2] Vanderbilt Univ, Med Ctr, Vanderbilt Ctr Neurosci Drug Discovery, Nashville, TN 37232 USA

[3] Vanderbilt Univ, Dept Chem, Nashville, TN 37232 USA

关键词: Metabotropic glutamate receptor 2;    Metabotropic glutamate receptor 3;    mGlu(2) receptor;    mGlu(3) receptor;    Negative allosteric modulator (NAM);   

DOI  :  10.1016/j.bmcl.2014.04.051

来源: Elsevier

【 摘 要 】

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 (mGlu(2) and mGlu(3), 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 mGlu(2)/mGlu(3) NAMs, with excellent selectivity versus the other mGluRs. (C) 2014 Elsevier Ltd. All rights reserved.

【 授权许可】

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