Discovery of 5-aryl-1, 3-dihydro-2H-imidazo[4, 5-b]pyridin-2-ones as positive allosteric modulators of metabotropic glutamate subtype-2 (mGlu2) receptors with efficacy in a preclinical model of psychosis. Issue 4 (15th February 2016)

• Record Type: Journal Article
• Authors: Layton, Mark E.; Reif, Alexander J.; Hartingh, Timothy J.; Rodzinak, Kevin; Dudkin, Vadim; Wang, Cheng; Arrington, Ken; Kelly, Michael J.; Garbaccio, Robert M.; O'Brien, Julie A.; Magliaro, Brian C.; Uslaner, Jason M.; Huszar, Sarah L.; Fillgrove, Kerry L.; Tang, Cuyue; Kuo, Yuhsin; Jacobson, Marlene A.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 4(2016)
• Page Start: 1260
• Page End: 1264
• Publication Date: 2016-02-15
• Subjects: PFISFKDVNQMIBD-UHFFFAOYSA-N -- LTMOLRJYCSLRSB-DFGRBFICSA-N -- ADXIKVSKCLYGHD-UHFFFAOYSA-N; Metabotropic glutamate receptor -- Positive allosteric modulator -- mGlu2 PAM -- Schizophrenia; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.01.021
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Optimization of a benzimidazolone template for potency and physical properties revealed 5-aryl-1, 3-dihydro-2 H -imidazo[4, 5- b ]pyridin-2-ones as a key template on which to develop a new series of mGlu2 positive allosteric modulators (PAMs). Systematic investigation of aryl-SAR led to the identification of compound27 as a potent and highly selective mGlu2 PAM with sufficient pharmacokinetics to advance to preclinical models of psychosis. Gratifyingly, compound27 showed full efficacy in the PCP- and MK-801-induced hyperlocomotion assay in rats at CSF concentrations consistent with mGlu2 PAM potency.