Starting from two weak mGlu receptor positive allosteric modulator (PAM) HTS hits ( and ), a molecular hybridization strategy resulted in the identification of a novel spiro-oxindole piperidine series with improved activity and metabolic stability. Scaffold hopping around the spiro-oxindole core identified the 3-(azetidin-3-yl)-1-benzimidazol-2-one as bioisoster. Medicinal chemistry optimization of these two novel chemotypes resulted in the identification of potent, selective, orally bioavailable, and brain penetrant mGluR PAMs.
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| http://dx.doi.org/10.1021/acsmedchemlett.9b00350 | DOI Listing |
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