Discovery of 1,5-Disubstituted Pyridones: A New Class of Positive Allosteric Modulators of the Metabotropic Glutamate 2 Receptor

Abstract

A series of 1,5-disubstituted pyridones was identified as positive allosteric modulators (PAMs) of the metabotropic glutamate receptor 2 (mGluR2) via high throughput screening (HTS). Subsequent SAR exploration led to the identification of several compounds with improved in vitro activity. Lead compound 8 was further profiled and found to attenuate the increase in PCP induced locomotor activity in mice.

Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives

“…Although several novel types of positive allosteric modulators have been discovered (XII-XVI in Table 8) (Zhang et al, 2008b;Duplantier et al, 2009;Brnardic et al, 2010;Cid et al, 2010;D'Alessandro et al, 2010;Tresadern et al, 2010), only few negative allosteric modulators of group II mGlu receptors are known. For two non-amino acid-based classes of group II antagonists Wichmann et al, 1999), it has not been clearly established whether they are competitive or allosteric.…”

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.…”

“…Scientists at Pfizer have reported their attempts to replace the benzimidazole core with benzothiazole, imidazopyridine or quinoline heterocycles; however, all these replacements were found to be detrimental for activity. The high clearance and low oral bioavailability found with the original Pfizer lead 47 were successfully addressed by the introduction of para substituents (48) in the distal aromatic ring as well as by the incorporation of pyridyl nitrogens (49). Introduction of the nitrogen into the benzofused ring to yield an aza-benzimidazole core was well tolerated for activity with many examples reported, the C 4 position being the more favourable for potency as illustrated with compound 50.…”

“…Representative hits were N-alkylpyridones substituted at either the C 5 (74) or C 4 (75) with an aromatic substituent [130]. Compound 76 [49], resulting from the optimization of hit 74, proved to be active in vivo in the PCP-locomotor activity model, suggesting antipsychotic-like activity.…”

Special Issue on the Pharmacology and Medicinal Chemistry of Allosteric Modulators of Metabotropic Glutamate Receptors (mGluRs)

“…Since the discovery and cloning in the late 1980s, eight mGlu receptor subtypes have been identified and divided into three groups: group I includes mGlu 1 and mGlu 5 , group II includes mGlu 2 and mGlu 3 , and group III consists of mGlu 4 , mGlu 6 , mGlu 7 , and mGlu 8 . 1 Targeting the orthosteric (glutamate binding site) has proven challenging to impossible for most mGluR subtypes, as ligands lack subtype selectivity and possess unfavorable physiochemical and DMPK properties.…”