【摘要】 磷酸二酯酶7和4（phosphodiesterase 7 and 4,PDE7 and PDE4）作为特异性水解第二信使3’,5’-环腺苷酸的蛋白酶,是治疗炎症等相关疾病的重要靶点。本文以37个噻吩并嘧啶酮类PDE7和PDE4双重抑制剂为研究对象,采用比较分子相似性指数分析（Co MSIA）,研究其影响化合物抑制活性的特征结构信息。结果表明,这两类抑制剂的Co MSIA的预测能力较强（Rpre2≥0.80）。其影响分子生物活性的共同特征结构主要是:（1）噻吩环上的R₂取代基为疏水场的敏感区域;（2）嘧啶酮环和R₃取代基的链接基益于采用含氢键供体的亲水性基团;（3）噻吩环所在区域益于引入包含氢键供体的基团。研究还发现,PDE7抑制剂的R₁和R₂取代基,分别适宜结合小体积的亲水性基团和大体积的基团。PDE4抑制剂的嘧啶酮环和R3取代基的链接基益于结合正电基团。本研究所得的模型和信息,可为后续新型抑制剂的设计开发提供理论指导。更多还原

【Abstract】 Phosphodiesterase 7 and 4（PDE7 and PDE4）,key enzymes specifically hydrolyzing the second messenger 3’,5’-cyclic adenosine monophosphate,are identified as drug targets for the treatment of many types of disease.The structural features of 37 thienopyrimidone derivatives as PDE7 and PDE4 inhibitors were explored by comparative molecular similarity indices analysis（Co MSIA） method herein.Two resultant Co MSIA models display a strong predictability（Rpre2≥0.80）.Meanwhile,the common structural features of these thienopyrimidone dual PDE7/PDE4 inhibitors are as follows:（1） R₂ part of the thiophene ring is the hydrophobic sensitive region;（2） the linker of pyrimidone and R3 moiety should select the hydrophilic and H-bond donor groups;（3） introduction of the H-bond donor groups into thiophene region is an excellent option.Furthermore,R₁ and R₂ moieties of PDE7 inhibitors tend tocombine small hydrophilic and bulky groups,respectively.The electropositive groups are conducive to the activity increase of PDE4 inhibitors.These models and the derived information may help to design novel dual PDE7/PDE4 inhibitors.更多还原