Discovery of 1,4-disubstituted 3-cyano-2-pyridones: a new class of positive allosteric modulators of the metabotropic glutamate 2 receptor

Journal of Medicinal Chemistry
José María CidAndrés A Trabanco

Abstract

The discovery and characterization of compound 48, a selective and in vivo active mGlu2 receptor positive allosteric modulator (PAM), are described. A key to the discovery was the rational exploration of the initial HTS hit 13 guided by an overlay model built with reported mGlu2 receptor PAM chemotypes. The initial weak in vitro activity of the hit 13 was quickly improved, although compounds still had suboptimal druglike properties. Subsequent modulation of the physicochemical properties resulted in compounds having a more balanced profile, combining good potency and in vivo pharmacokinetic properties. Final refinement by addressing cardiovascular safety liabilities led to the discovery of compound 48. Besides good potency, selectivity, and ADME properties, compound 48 displayed robust in vivo activity in a sleep-wake electroencephalogram (sw-EEG) assay consistent with mGlu2 receptor activation, in accordance with previous work from our laboratories.

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Citations

Mar 18, 2016·ACS Medicinal Chemistry Letters·Joseph E PeroMarlene A Jacobson
Mar 5, 2013·Expert Opinion on Therapeutic Patents·Andrés A Trabanco, José María Cid
Aug 5, 2014·Journal of Molecular Graphics & Modelling·Gary TresadernAndrés A Trabanco
Nov 8, 2016·Gene Expression Patterns : GEP·Caitlin E McOmishJay A Gingrich
Aug 9, 2019·Current Topics in Medicinal Chemistry·Zoltán OrgovánGyörgy M Keserű
Mar 23, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Claudia Llinas Del TorrentGary Tresadern
Aug 14, 2020·Journal of Agricultural and Food Chemistry·Tao ChenGuang-Fu Yang
Mar 19, 2020·ACS Medicinal Chemistry Letters·Ana Isabel de LucasJosé María Cid
Nov 28, 2017·Journal of Chemical Information and Modeling·Gary TresadernGerard J P van Westen

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