Dai Yujia, Guo Yan, Frey Robin R, Ji Zhiqin, Curtin Michael L, Ahmed Asma A, Albert Daniel H, Arnold Lee, Arries Shannon S, Barlozzari Teresa, Bauch Joy L, Bouska Jennifer J, Bousquet Peter F, Cunha George A, Glaser Keith B, Guo Jun, Li Junling, Marcotte Patrick A, Marsh Kennan C, Moskey Maria D, Pease Lori J, Stewart Kent D, Stoll Vincent S, Tapang Paul, Wishart Neil, Davidsen Steven K, Michaelides Michael R
Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6100, USA.
J Med Chem. 2005 Sep 22;48(19):6066-83. doi: 10.1021/jm050458h.
A series of novel thienopyrimidine-based receptor tyrosine kinase inhibitors has been discovered. Investigation of structure-activity relationships at the 5- and 6-positions of the thienopyrimidine nucleus led to a series of N,N'-diaryl ureas that potently inhibit all of the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptor tyrosine kinases. A kinase insert domain-containing receptor (KDR) homology model suggests that these compounds bind to the "inactive conformation" of the enzyme with the urea portion extending into the back hydrophobic pocket adjacent to the adenosine 5'-triphosphate (ATP) binding site. A number of compounds have been identified as displaying excellent in vivo potency. In particular, compounds 28 and 76 possess favorable pharmacokinetic (PK) profiles and demonstrate potent antitumor efficacy against the HT1080 human fibrosarcoma xenograft tumor growth model (tumor growth inhibition (TGI) = 75% at 25 mg/kg.day, per os (po)).
已发现一系列新型的基于噻吩并嘧啶的受体酪氨酸激酶抑制剂。对噻吩并嘧啶核5位和6位的构效关系进行研究后，得到了一系列N,N'-二芳基脲，它们能有效抑制所有血管内皮生长因子（VEGF）和血小板衍生生长因子（PDGF）受体酪氨酸激酶。含激酶插入结构域受体（KDR）同源模型表明，这些化合物与酶的“非活性构象”结合，脲部分延伸至与腺苷5'-三磷酸（ATP）结合位点相邻的后疏水口袋中。已鉴定出多种化合物在体内具有优异的活性。特别是，化合物28和76具有良好的药代动力学（PK）特征，并在HT1080人纤维肉瘤异种移植肿瘤生长模型中显示出强大的抗肿瘤功效（口服（po），25 mg/kg·天，肿瘤生长抑制（TGI）= 75%）。
