Fragment and Structure-Based Drug Discovery for a Class C GPCR: Discovery of the mGlu<sub>5</sub> Negative Allosteric Modulator HTL14242 (3-Chloro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile)

Fragment screening of a thermostabilized mGlu<sub>5</sub> receptor using a high-concentration radioligand binding assay enabled the identification of moderate affinity, high ligand efficiency (LE) pyrimidine hit <b>5</b>. Subsequent optimization using structure-based drug discovery methods led to the selection of <b>25</b>, HTL14242, as an advanced lead compound for further development. Structures of the stabilized mGlu<sub>5</sub> receptor complexed with <b>25</b> and another molecule in the series, <b>14</b>, were determined at resolutions of 2.6 and 3.1 Å, respectively.