Synthesis and SAR of substituted pyrazolo[1,5-a]quinazolines as dual mGlu2/mGlu3 NAMs |
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| Affiliation: | 1. Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA;2. Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA;3. Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA;1. Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, United States;2. Neuroscience Discovery Biology, Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, United States;1. College of Pharmacy, BIO5 Oro Valley, The University of Arizona, Oro Valley, AZ 85737, United States;2. Department of Chemistry and Biochemistry, The University of Arizona, Tucson, AZ 85721, United States |
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| Abstract: | 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. |
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| Keywords: | Metabotropic glutamate receptor 2 Metabotropic glutamate receptor 3 Negative allosteric modulator (NAM) |
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