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

Abstract

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.

E7090, a Novel Selective Inhibitor of Fibroblast Growth Factor Receptors, Displays Potent Antitumor Activity and Prolongs Survival in Preclinical Models

“…E7090, E7090 succinate, AZD4547, ponatinib, and PD173074 were synthesized at Eisai Co. Ltd., in accordance with previously reported procedures (18,19) and are described in patent publications WO 2014129477 (US 20140235614), WO 2016027781, WO 2008075068, and WO 2007075869. For in vitro studies, all compounds were prepared as a 20 mmol/L stock solution in DMSO and diluted in the relevant assay media.…”

Analysis of water patterns in protein kinase binding sites

“…The ligand displacing WAT A11 and WAT A12 is PD173074, a potent and selective inhibitor of FGFR tyrosine kinase, with an IC 50 value of approximately 28 n M ,36 in contrast to its IC 50 values against platelet‐derived growth factor receptor (PDGFR) and Src tyrosine kinases of 14 and 20 μ M , respectively 36, 37. The crystal structure of PD173074 bound to FGFR1 (PDB code 2FGI)37 shows that the 3,5‐dimethoxyphenyl moiety projects into the back pocket of the kinase, with one methoxy oxygen replacing the hydrogen bond of WAT A12 to the backbone NH of Asp 641, and its methyl group filling the nearby small hydrophobic pocket.…”

Fibroblast Growth Factor Receptor Inhibitors

“…A series of novel Indolinone derivatives were discovered as a result of random-screening approach towards a small molecule library against various RTKs [67][68][69][70][71][72]. Using random screening approach, 3-substituted indolin-2-ones (9) were discovered as novel and selective VEGFR inhibitors ( Table 4).…”