Discovery of novel positive allosteric modulators of the metabotropic glutamate receptor 5 (mGlu5)

Novel in vitro mGlu5 positive allosteric modulators with good potency, solubility, and low lipophilicity are described. Compounds were identified which did not rely on the phenylacetylene and carbonyl functionalities previously observed to be required for in vitro activity. Investigation of the allosteric binding requirements of a series of dihydroquinolinone analogs led to phenylacetylene azachromanone 4 (EC50 11.5 nM). Because of risks associated with potential metabolic and toxicological liabilities of the phenylacetylene, this moiety was successfully replaced with a phenoxymethyl group (27; EC50 156.3 nM). Derivation of a second-generation of mGlu5 PAMs lacking a ketone carbonyl resulted in azaindoline (33), azabenzimidazole (36), and N-methyl 8-azaoxazine (39) phenylacetylenes. By scoping nitrogen substituents and phenylacetylene replacements in 39, we identified phenoxymethyl 8-azaoxazine 47 (EC50 50.1 nM) as a potent and soluble mGlu5 PAM devoid of both undesirable phenylacetylene and carbonyl functionalities.

Positive allosteric modulators of mGlu5 are described.Figure optionsDownload as PowerPoint slide