New anilinophthalazines as potent and orally well absorbed inhibitors of the VEGF receptor tyrosine kinases useful as antagonists of tumor-driven angiogenesis
New anilinophthalazines as potent and orally well absorbed inhibitors of the VEGF receptor tyrosine kinases useful as antagonists of tumor-driven angiogenesis
复制标题
DOI：
10.1021/jm9909443
复制
发表时间：
2000-06-15
影响因子：
7.3
通讯作者：
Wood, JM
中科院分区：
文献类型：
--
作者：
Bold, G;Altmann, KH;Wood, JM
新血管的萌芽或血管生成，对于任何实体肿瘤来说都是必要的，才能长得足够大，从而导致危及生命的疾病。血管内皮生长因子(VEGF)是肿瘤诱导血管生成的关键促进剂之一。血管内皮生长因子受体，即酪氨酸激酶Flt-1和KDR，表达于血管内皮细胞，经VE-GF激活后启动血管生成。CGP 79787D(或PTK787/ZK222584)可逆地抑制Flt-1和KDR，其IC50值为0.1mU；CGP 79787D还可阻断异位表达KDR受体的CHO细胞中血管内皮生长因子诱导的受体自磷酸化作用(ED50=34 nM)。与相关受体酪氨酸激酶PDGF-R和c-Kit相比，1-苯胺基修饰提供了对VEGF受体酪氨酸激酶Flt-1和KDR具有更高选择性的衍生物。由于这些1-苯胺基-(4-吡啶甲基)二氮杂氮在口服中吸收良好，这些化合物有资格进一步分析，并作为临床评估的候选者。
The sprouting of new blood vessels, or angiogenesis, is necessary for any solid tumor to grow large enough to cause life-threatening disease. Vascular endothelial growth factor (VEGF) is one of the key promoters of tumor induced angiogenesis. VEGF receptors, the tyrosine kinases Flt-1 and KDR, are expressed on vascular endothelial cells and initiate angiogenesis upon activation by VE GF. 1-Anilino-(4-pyridylmethyl)-phthalazines, such as CGP 79787D (or PTK787 / ZK222584), reversibly inhibit Flt-1 and KDR with IC50 values < 0.1 mu M CGP 79787D also blocks the VEGF-induced receptor autophosphorylation in CHO cells ectopically expressing the KDR receptor (ED50 = 34 nM). Modification of the 1-anilino moiety afforded derivatives with higher selectivity for the VEGF receptor tyrosine kinases Flt-1 and KDR compared to the related receptor tyrosine kinases PDGF-R and c-Kit. Since these 1-anilino-(4-pyridylmethyl)phthalazines are orally well absorbed, these compounds qualify for further profiling and as candidates for clinical evaluation.