文摘
Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGlub>5b>) represent a promising therapeutic strategy for the treatment of schizophrenia. Starting from an acetylene-based lead from high throughput screening, an evolved bicyclic dihydronaphthyridinone was identified. We describe further refinements leading to both dihydronaphthyridinone and tetrahydronaphthyridine mGlub>5b> PAMs containing an alkoxy-based linkage as an acetylene replacement. Exploration of several structural features including western pyridine ring isomers, positional amides, linker connectivity/position, and combinations thereof, reveal that these bicyclic modulators generally exhibit steep SAR and within specific subseries display a propensity for pharmacological mode switching at mGlub>5b> as well as antagonist activity at mGlub>3b>. Structure鈥揳ctivity relationships within a dihydronaphthyridinone subseries uncovered <b>12cb> (VU0405372), a selective mGlub>5b> PAM with good in vitro potency, low glutamate fold-shift, acceptable DMPK properties, and in vivo efficacy in an amphetamine-based model of psychosis.