摘要
支气管哮喘和慢性阻塞性肺疾病(COPD)是常见的呼吸系统疾病,但是现在尚无有效的治疗药物~([1,2])。儿茶酚醚类衍生物作为最早的磷酸二酯酶IV抑制剂被广泛应用,但是经典的PDE4抑制剂rolipram等会引起呕吐、恶心等副作用~([3])。本课题组以rolipram等为先导化合物,借助计算机辅助药物设计等手段建立了该类化合物的药效团,然后利用生物电子等排体原理及构象限制等药物设计的基本方法进行骨架越迁,设计合成了系列以四氢异喹啉为骨架的新型选择性PDE4抑制剂。初步构效关系表明酰胺键为活性必需基团,芳香环有助于提高生物活性。
Nowadays asthma and chronic obstructive pulmonary diseases(COPD) known as the kind of chronic obstructive lung disease have been a major public health burden worldwide.But there is no effective drug for treating asthma and COPD.The diether derivative of catechol class as the important type of selective PDE4 inhibitors such as rolipram is one of the earliest and most extensively studied PDE4 inhibitors.Our focus was placed on the design and synthesis of 7-(cyclopentyloxy)-6-methoxyl,2,3,4-tetrahydroisoquinoline derivatives based on scaffold hopping through bioisosteres and conformational restriction theories.A primary structure-activity relationship study showed that carbonyl group and aromatic ring in the molecule were favored to the bioactivity.
引文
[1]Rodrigo,G.J.;Plaza,V.Chest.2014,146:309.
[2]Raghavan,N.;Webb,K.;Amomputtisathaporn,N.;O'Donnell,D.E.Curr.Opin.Pharmacol.2010,26:1051.
[3]Song,G.P.;Zhao,D.S.;Hu,D.K.;Li,Y.S.;Jin,H.W.;Cui,Z.N.Bioorg.Med.Chem.Lett.2015,25:4610.