Positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4): Part I. Discovery of pyrazolo[3,4-d]pyrimidines as novel mGluR4 positive allosteric modulators

This letter describes the synthesis and SAR, developed through an iterative analogue library approach, of an mGluR4 positive allosteric modulator lead based on a pyrazolo[3,4-d]pyrimidine scaffold. Despite tremendous therapeutic potential, Compound 7, VU0080421, and related congeners represent only a handful of mGluR4 positive allosteric modulators ever described.

Graphical abstractThe synthesis and SAR of a novel mGluR4 positive allosteric modulator 7, VU0080241, is described. VU0080241 displayed an EC50 of 4.6 μM and shifted the glutamate response curve 11.8- to 27-fold to the left.Figure optionsDownload full-size imageDownload as PowerPoint slide