Discovery of 4‑(5-Membered)Heteroarylether-6-methylpicolinamide\nNegative Allosteric Modulators of Metabotropic Glutamate Receptor\nSubtype 5

This Letter details\nour efforts to develop novel, non-acetylene-containing\nmetabotropic glutamate receptor subtype 5 (mGlu<sub>5</sub>) negative\nallosteric modulators (NAMs) with improved pharmacological properties.\nThis endeavor involved replacing the ether-linked pyrimidine moiety,\na metabolic liability, with various 5-membered heterocycles. From\nthis exercise, we identified <b>VU6043653</b>, a highly brain\npenetrant and selective mGlu<sub>5</sub> NAM which displayed moderate\npotency against both human and rat mGlu<sub>5</sub>. Moreover, <b>VU6043653</b> has overall improved pharmacological and drug metabolism\nand pharmacokinetic profiles when compared to its predecessor compounds.\nMost notably, <b>VU6043653</b> exhibits low predicted human\nhepatic clearance, a clean cytochrome P450 profile, and minimal inhibition\nof the dopamine transporter.