DihydrothiazolopyridoneDerivatives as a Novel Familyof Positive Allosteric Modulators of the Metabotropic Glutamate 5(mGlu5) Receptor.

Startingfrom a singleton chromanone high throughput screening(HTS) hit, we describe a focused medicinal chemistry optimizationeffort leading to the identification of a novel series of phenoxymethyl-dihydrothiazolopyridonederivatives as selective positive allosteric modulators (PAMs) ofthe metabotropic glutamate 5 (mGlu5) receptor. These dihydrothiazolopyridonespotentiate receptor responses in recombinant systems. In vitro andin vivo drug metabolism and pharmacokinetic (DMPK) evaluation allowedus to select compound 16afor its assessment in a preclinicalanimal screen of possible antipsychotic activity. 16awas able to reverse amphetamine-induced hyperlocomotion in ratsin a dose-dependent manner without showing any significant motor impairmentor overt neurological side effects at comparable doses. Evolutionof our medicinal chemistry program, structure activity, and propertiesrelationships (SAR and SPR) analysis as well as a detailed profilefor optimized mGlu5receptor PAM 16aare described. [ABSTRACT FROM AUTHOR]