Synthesis, Structural Analysis, and Biological Evaluation of Thioxoquinazoline Derivatives as Phosphodiesterase 7 Inhibitors
Synthesis, Structural Analysis, and Biological Evaluation of Thioxoquinazoline Derivatives as Phosphodiesterase 7 Inhibitors
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DOI：
10.1002/cmdc.200900043
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发表时间：
2009-05-01
期刊：
影响因子：
3.4
通讯作者：
Gil, Carmen
中科院分区：
文献类型：
--
作者：
Castano, Tania;Wang, Huanchen;Gil, Carmen
PDE 7抑制剂调节促炎和免疫T细胞功能，并且是一类潜在的新型药物，特别适用于治疗各种免疫和炎性疾病。从硫代喹唑啉衍生物出发，设计、合成并表征了一系列新型的硫代喹唑啉衍生物。这些化合物中的许多在亚微摩尔水平下对PDE 7A 1的催化结构域显示出抑制效力，并且在微摩尔水平下对PDE 4D 2显示出抑制效力。基于细胞的研究表明，这些化合物不仅增加了细胞内cAMP水平，而且在治疗窗口内具有有趣的抗炎特性。计算机模拟数据预测这些化合物能够穿过血脑屏障。与化合物15复合的PDE 7A 1催化结构域的X射线晶体结构在2.4埃的分辨率下证明活性位点口袋处的疏水相互作用是关键特征。该结构与分子建模一起提供了对PDE抑制剂的选择性的深入了解，并为发现新的PDE 7或PDE 7/PDE 4双重抑制剂提供了模板。
PDE7 inhibitors regulate pro-inflammatory and immune T cell functions,and are a potentially novel class of drugs especially useful in the treatment of a wide variety of immune and inflammatory disorders. Starting from our lead family of thioxoquinazolines, we designed, synthesized, and characterized a novel series of thioxoquinazoline derivatives. Many of these compounds showed inhibitory potencies at sub-micromolar levels against the catalytic domain of PDE7A1 and at the micromolar level against PDE4D2. Cell-based studies showed that these compounds not only increased intracellular cAMP levels, but also had interesting anti-inflammatory properties within a therapeutic window. The in silico data predict that these compounds are capable of the crossing the blood-brain barrier. The X-ray crystal structure of the PDE7A1 catalytic domain in complex with compound 15 at a resolution of 2.4 angstrom demonstrated that hydrophobic interactions at the active site pocket are a key feature. This structure, together with molecular modeling, provides insight into the selectivity of the PDE inhibitors and a template for the discovery of new PDE7 or PDE7/PDE4 dual inhibitors.