Discovery of <i>N</i>‑(5-Fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide (VU0424238): A Novel Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 5 Selected for Clinical Evaluation

Preclinical evidence in support of the potential utility of mGlu5 NAMs for the treatment of a variety of psychiatric and neurodegenerative disorders is extensive, and multiple such molecules have entered clinical trials. Despite some promising results from clinical studies, no small molecule mGlu5 NAM has yet to reach market. Here we present the discovery and evaluation of N-(5-fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)­picolinamide (27, VU0424238), a compound selected for clinical evaluation. Compound 27 is more than 900-fold selective for mGlu5 versus the other mGlu receptors, and binding studies established a Ki value of 4.4 nM at a known allosteric binding site. Compound 27 had a clearance of 19.3 and 15.5 mL/min/kg in rats and cynomolgus monkeys, respectively. Imaging studies using a known mGlu5 PET ligand demonstrated 50% receptor occupancy at an oral dose of 0.8 mg/kg in rats and an intravenous dose of 0.06 mg/kg in baboons.支持代谢型谷氨酸受体5负变构调节剂（mGlu5 NAMs）用于治疗多种精神疾病与神经退行性疾病的临床前证据十分充分，且已有多款此类分子进入临床试验阶段。尽管临床研究已取得若干颇具前景的成果，但目前尚无一款小分子mGlu5 NAM获批上市。本研究报道了N-(5-氟吡啶-2-基)-6-甲基-4-(嘧啶-5-氧基)吡啶甲酰胺（27，VU0424238）的发现与评价过程，该化合物已被遴选进入临床评估阶段。相较于其他代谢型谷氨酸受体，化合物27对mGlu5的选择性高达900倍以上；结合实验证实其在已知变构结合位点的抑制常数（Ki）为4.4 nM。化合物27在大鼠和食蟹猴体内的血浆清除率分别为19.3 mL/min/kg与15.5 mL/min/kg。采用已知mGlu5正电子发射断层扫描（PET）配体开展的成像研究显示：大鼠经口给予0.8 mg/kg剂量时，受体占有率可达50%；狒狒静脉给予0.06 mg/kg剂量时，受体占有率同样达到50%。