Thompson Andrew M, Delaney Amy M, Hamby James M, Schroeder Mel C, Spoon Teresa A, Crean Sheila M, Showalter H D Hollis, Denny William A
Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, New Zealand.
J Med Chem. 2005 Jul 14;48(14):4628-53. doi: 10.1021/jm0500931.
7-Substituted 3-aryl-1,6-naphthyridine-2,7-diamines and related 2-ureas are inhibitors of fibroblast growth factor receptor-1 (FGFR-1) and vascular endothelial growth factor receptor-2 (VEGFR-2). 3-(3,5-Dimethoxyphenyl) and 3-phenyl analogues were prepared from 7-acetamido-2-tert-butylureas by alkylation with benzyl omega-iodoalkyl ethers, debenzylation, and amination, followed by selective cleavage of the 7-N-acetamide. 3-(2,6-Dichlorophenyl) analogues were prepared from the 7-fluoro-2-amine by displacement with substituted alkylamines, followed by selective acylation of the resulting substituted naphthyridine-2,7-diamines with alkyl isocyanates. The 3-(3,5-dimethoxyphenyl) derivatives were low nanomolar inhibitors of both FGFR and VEGFR and were highly selective (>100-fold) over PDGFR and c-Src. Variations in the base strength or spatial position of the 7-side chain base had only small effects on the potency (<5-fold) or selectivity (<20-fold). The 3-(2,6-dichlorophenyl)-2-urea derivatives were slightly less active against VEGFR and less selective, being more effective against PDGFR (ca. 10-fold) and c-Src (ca. 500-fold). The 3-(3,5-dimethoxyphenyl)-1,6-naphthyridines were generally more potent than the corresponding pyrido[2,3-d]pyrimidines against both VEGFR and FGFR (2- to 20-fold), with only slightly increased PDGFR and c-Src activity. The 3-(3,5-dimethoxyphenyl)-1,6-naphthyridine 2-ureas were also low nanomolar inhibitors of the growth of human umbilical vein endothelial cells (HUVECs) stimulated by serum, FGF, or VEGF, at concentrations that did not affect the growth of representative tumor cell lines, and were more (3- to 65-fold) potent than the corresponding pyrido[2,3-d]pyrimidines.
7-取代的3-芳基-1,6-萘啶-2,7-二胺及相关的2-脲类化合物是成纤维细胞生长因子受体-1（FGFR-1）和血管内皮生长因子受体-2（VEGFR-2）的抑制剂。3-(3,5-二甲氧基苯基)和3-苯基类似物由7-乙酰氨基-2-叔丁基脲与苄基ω-碘代烷基醚进行烷基化反应、脱苄基反应和胺化反应制备，随后选择性裂解7-N-乙酰酰胺。3-(2,6-二氯苯基)类似物由7-氟-2-胺与取代烷基胺进行取代反应制备，随后用烷基异氰酸酯对所得的取代萘啶-2,7-二胺进行选择性酰化反应。3-(3,5-二甲氧基苯基)衍生物对FGFR和VEGFR均为低纳摩尔级抑制剂，对血小板衍生生长因子受体（PDGFR）和c-Src具有高度选择性（>100倍）。7-侧链碱基的碱强度或空间位置的变化对活性（<5倍）或选择性（<20倍）的影响很小。3-(2,6-二氯苯基)-2-脲衍生物对VEGFR的活性略低，选择性也较差，对PDGFR（约10倍）和c-Src（约500倍）更有效。3-(3,5-二甲氧基苯基)-1,6-萘啶对VEGFR和FGFR的活性通常比相应的吡啶并[2,3-d]嘧啶更高（2至20倍），对PDGFR和c-Src的活性仅略有增加。3-(3,5-二甲氧基苯基)-1,6-萘啶-2-脲在不影响代表性肿瘤细胞系生长的浓度下，也是血清、成纤维细胞生长因子（FGF）或血管内皮生长因子（VEGF）刺激的人脐静脉内皮细胞（HUVECs）生长的低纳摩尔级抑制剂，并且比相应的吡啶并[2,3-d]嘧啶更有效（3至65倍）。
