Synthesis and structure-activity relationships of soluble 7-substituted 3-(3,5-dimethoxyphenyl)-1,6-naphthyridin-2-amines and related ureas as dual inhibitors of the fibroblast growth factor receptor-1 and vascular endothelial growth factor receptor-2 tyrosine kinases.
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.
Thompson
Andrew M
AM
Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, New Zealand. am.thompson@auckland.ac.nz
Delaney
Amy M
AM
Hamby
James M
JM
Schroeder
Mel C
MC
Spoon
Teresa A
TA
Crean
Sheila M
SM
Showalter
H D Hollis
HD
Denny
William A
WA
D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors*; D012995:Solubility; D013329:Structure-Activity Relationship; D014471:Umbilical Veins / Q000166:cytology; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
D020533:Angiogenesis Inhibitors; D009287:Naphthyridines; D017468:Receptors, Fibroblast Growth Factor; D014508:Urea; C496348:FGFR1 protein, human; C496350:Fgfr1 protein, rat; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D040301:Vascular Endothelial Growth Factor Receptor-2