Identification of a Novel Orally Bioavailable Phosphodiesterase 10A (PDE10A) Inhibitor with Efficacy in Animal Models of Schizophrenia.

We report the continuation of a focused medicinal chemistry program aimed to further optimize a series of imidazo­[1,2-<i>a</i>]­pyrazines as a novel class of potent and selective phosphodiesterase 10A (PDE10A) inhibitors. In vitro and in vivo pharmacokinetic and pharmacodynamic evaluation allowed the selection of compound <b>25a</b> for its assessment in preclinical models of psychosis. The evolution of our medicinal chemistry program, structure–activity relationship (SAR) analysis, as well as a detailed pharmacological profile for optimized lead <b>25a</b> are described

Discovery of VU0409551/JNJ-46778212: An mGlu₅ Positive Allosteric Modulator Clinical Candidate Targeting Schizophrenia

Herein, we report the structure–activity relationship of a novel series of (2­(phenoxymethyl)-6,7-dihydrooxazolo­[5,4-<i>c</i>]­pyridine-5­(4<i>H</i>)-yl­(aryl)­methanones as potent, selective, and orally bioavailable metabotropic glutamate receptor subtype 5 (mGlu₅) positive allosteric modulators (PAMs). On the basis of its robust <i>in vitro</i> potency and <i>in vivo</i> efficacy in multiple preclinical models of multiple domains of schizophrenia, coupled with a good DMPK profile and an acceptable therapeutic window, <b>17a</b> (VU0409551/JNJ-46778212) was selected as a candidate for further development

Tetrahydronaphthyridine and Dihydronaphthyridinone Ethers As Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 5 (mGlu₅)

Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGlu₅) 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 mGlu₅ 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 mGlu₅ as well as antagonist activity at mGlu₃. Structure–activity relationships within a dihydronaphthyridinone subseries uncovered <b>12c</b> (VU0405372), a selective mGlu₅ PAM with good in vitro potency, low glutamate fold-shift, acceptable DMPK properties, and in vivo efficacy in an amphetamine-based model of psychosis