Discovery and structure–activity relationship of 1,3-cyclohexyl amide derivatives as novel mGluR5 negative allosteric modulators

The design, syntheses and structure–activity relationships (SAR) of novel 1,3-cyclohexyl amide derivatives as mGluR5 negative allosteric modulators are described. A novel series of trans-1,3-cyclohexyl diamides was discovered and characterized as mGluR5 negative allosteric modulators (NAMs) lacking an alkyne moiety. Conformational constraint of one of the amide bonds in the diamide template led to a spirooxazoline template. A representative compound (24d) showed good in vitro potency, high CNS penetration and, upon subcutaneous dosing, demonstrated efficacy in the mouse marble burying test, generally used as indicative of potential anxiolytic activity.