Design, synthesis and pharmacological evaluation of novel polycyclic heteroarene ethers as PDE10A inhibitors: Part II
Design, synthesis and pharmacological evaluation of novel polycyclic heteroarene ethers as PDE10A inhibitors: Part II
复制标题
DOI：
10.1016/j.bmcl.2014.06.028
复制
发表时间：
2014-08-01
影响因子：
2.7
通讯作者：
Thomas, Abraham
中科院分区：
文献类型：
--
作者：
Das, Sanjib;Shelke, Dnyaneshwar E.;Thomas, Abraham
本文设计合成了一种新型吡咯[3,2-b]喹啉类杂芳烃醚类PDE10A抑制剂，具有良好的效价、选择性和代谢稳定性。进一步优化后，鉴定出1-甲基-3-（4-{[3-（吡啶-4-基）吡嗪-2-基]氧}苯基）- 1h -pyrrolo[3,2-b]吡啶13a，具有良好的hPDE10A效价（IC50: 6.3 nM），对其他相关PDEs具有良好的选择性和理想的物理化学性质。该化合物在啮齿类动物口服剂量后表现出高外周和足够的脑水平。该化合物在与精神疾病，特别是精神分裂症相关的多种临床前动物模型中也显示出优异的疗效。(C) 2014 Elsevier Ltd.版权所有。
We report the design and synthesis of novel pyrrolo[3,2-b]quinoline containing heteroarene ethers as PDE10A inhibitors with good to excellent potency, selectivity and metabolic stability. Further optimization of this primary series resulted in the identification of 1-methyl-3-(4-{[3-(pyridine-4-yl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrolo[3,2-b]pyridine 13a with good hPDE10A potency (IC50: 6.3 nM), excellent selectivity over other related PDEs and desirable physicochemical properties. The compound exhibited high peripheral and adequate brain levels upon oral dosing in rodents. The compound also showed excellent efficacy in multiple preclinical animal models related to psychiatric disorders, particularly schizophrenia. (C) 2014 Elsevier Ltd. All rights reserved.