Design of 4-Oxo-1-aryl-1,4-dihydroquinoline-3-carboxamides as Selective Negative Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 2

Andrew S. Felts, Alice L. Rodriguez, Katrina A. Smith, Julie L. Engers, Ryan D. Morrison, Frank W. Byers, Anna L. Blobaum, Charles W. Locuson, Sichen Chang, Daryl F. Venable, Colleen M. Niswender, J. Scott Daniels, P. Jeffrey Conn, Craig W. Lindsley, Kyle A. Emmitte

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21 Scopus citations

Abstract

Both orthosteric and allosteric antagonists of the group II metabotropic glutamate receptors (mGlus) have been used to establish a link between mGlu2/3 inhibition and a variety of CNS diseases and disorders. Though these tools typically have good selectivity for mGlu2/3 versus the remaining six members of the mGlu family, compounds that are selective for only one of the individual group II mGlus have proved elusive. Herein we report on the discovery of a potent and highly selective mGlu2 negative allosteric modulator 58 (VU6001192) from a series of 4-oxo-1-aryl-1,4-dihydroquinoline-3-carboxamides. The concept for the design of this series centered on morphing a quinoline series recently disclosed in the patent literature into a chemotype previously used for the preparation of muscarinic acetylcholine receptor subtype 1 positive allosteric modulators. Compound 58 exhibits a favorable profile and will be a useful tool for understanding the biological implications of selective inhibition of mGlu2 in the CNS.

Original languageEnglish
Pages (from-to)9027-9040
Number of pages14
JournalJournal of Medicinal Chemistry
Volume58
Issue number22
DOIs
StatePublished - 25 Nov 2015

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    Felts, A. S., Rodriguez, A. L., Smith, K. A., Engers, J. L., Morrison, R. D., Byers, F. W., Blobaum, A. L., Locuson, C. W., Chang, S., Venable, D. F., Niswender, C. M., Daniels, J. S., Conn, P. J., Lindsley, C. W., & Emmitte, K. A. (2015). Design of 4-Oxo-1-aryl-1,4-dihydroquinoline-3-carboxamides as Selective Negative Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 2. Journal of Medicinal Chemistry, 58(22), 9027-9040. https://doi.org/10.1021/acs.jmedchem.5b01371