Discovery of N-(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.
Discovery of N-(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.
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DOI：
10.1021/acs.jmedchem.7b00410
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发表时间：
2017-06-22
影响因子：
7.3
通讯作者：
Emmitte KA
中科院分区：
文献类型：
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作者：
Felts AS;Rodriguez AL;Blobaum AL;Morrison RD;Bates BS;Thompson Gray A;Rook JM;Tantawy MN;Byers FW;Chang S;Venable DF;Luscombe VB;Tamagnan GD;Niswender CM;Daniels JS;Jones CK;Conn PJ;Lindsley CW;Emmitte KA
支持mGlu 5 NAM用于治疗各种精神和神经退行性疾病的潜在效用的临床前证据是广泛的，并且多种这样的分子已经进入临床试验。尽管临床研究取得了一些有希望的结果，但还没有小分子mGlu 5 NAM进入市场。在这里，我们提出了N-（5-氟吡啶-2-基）-6-甲基-4-（嘧啶-5-基氧基）吡啶酰胺（27，VU 0424238）的发现和评价，这是一种选择用于临床评价的化合物。化合物27对mGlu 5的选择性是其他mGlu受体的900倍以上，结合研究在已知的变构结合位点建立了4.4 nM的Ki值。化合物27在大鼠和食蟹猴中分别具有19.3和15.5mL/min/kg的清除率。使用已知mGlu 5 PET配体的成像研究表明，大鼠口服剂量为0.8 mg/kg时，受体占有率为50%，狒狒静脉注射剂量为0.06 mg/kg时，受体占有率为50%。
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.