Discovery of 1,4-Disubstituted 3-Cyano-2-pyridones: A New Class of Positive Allosteric Modulators of the Metabotropic Glutamate 2 Receptor

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.

Molecular determinants of positive allosteric modulation of the human metabotropic glutamate receptor 2

“…After thawing, membranes were homogenized using an Ultra Turrax homogenizer and suspended in ice-cold binding buffer containing 50 mM Tris-HCl (pH 7.4), 10 mM MgCl2, and 2 mM CaCl2; 75 μg membrane protein, test compound and 10 nM [ 3 H]-JNJ-40068782 were incubated for 60 min at RT, in a total volume of 0.5 mL. Non-specific binding (about 30% of total binding) was determined in the presence of 10 μM JNJ-40264796 (a mGlu2 PAM structurally related to JNJ-40068782, molecule 34 from Cid et al, 2012a). Filtration was performed using Unifilter-96 GF/C filters pre-soaked in 0.1% PEI and a 40-well manifold or 96-well Brandell harvester.…”

“…These compounds are selective for mGlu 2 receptors and have efficacy in animal models of antipsychotic activity similar to that seen with mGlu 2/3 receptor agonists (Galici et al ., ). The number of reports on mGlu 2 receptor PAM chemical series has increased over recent years (Trabanco et al ., , Trabanco and Cid, ) including multiple lead series from our laboratories (Cid‐Nuñez et al ., 2008b; 2010b; Tresadern et al ., ; Trabanco et al ., 2011c; 2012; Cid et al ., 2012a,b).…”

Metabotropic Glutamate Receptor 2 Activators

“…[38] Since the discovery of LY487379 and BINA and up to early 2009, a variety of structurally diverse chemotypes were published in both patent applications and research journals. Thus, shortly after the publication of LY487379, series such as acetophenones [44][45][46][47], indoles [48], 1,5-pyridones [49], 1,4-pyridones [50], isoindolones [51,52], pyrazolones [53], thienopyrimidines [54], oxazolidinones [55,56], benzimidazoles [57][58][59] and oxazolopyrimidones [60], were reported as novel mGlu2 receptor PAM chemotypes. For detailed background information, we refer to the reviews by Sheffler [61], Rudd and McCauley [62], Fraley [63], Marek [64] and Trabanco [65,66], which cover literature and patent applications.…”

“…Exploration at the C 4 position led to the identification of a diverse set of substituents that essentially can be grouped into three main different subclasses: (1) biarylethers (77) [50,131], (2) (Fig. 31).…”

Developmental expression of mGlu2 and mGlu3 in the mouse brain

“…This is largely due to the fact that mGlu2 and mGlu3 are highly conserved, and subtype-specific ligands have only recently been identified (Sheffler et al, 2010; Cid et al, 2012). Attempts to dissociate mGlu2 from mGlu3 suggest distinct roles and interactions for each subtype (Spooren et al, 2000; Linden et al, 2005; Hetzenauer et al, 2008).…”