1. 3-(3,5-Dimethoxyphenyl)-1,6-naphthyridine-2,7-diamines and Related 2-Urea Derivatives Are Potent and Selective Inhibitors of the FGF Receptor-1 Tyrosine Kinase
- Author
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Wayne Klohs, Denise L. Driscoll, Aneesa M. Amar, Wilbur R. Leopold, H. D. Hollis Showalter, Brian G. Hartl, William L. Elliott, Bill J. Roberts, Stacey L. Boushelle, Andrew M. Thompson, Randall W. Steinkampf, Connolly Cleo, Patrick W. Vincent, William A. Denny, James M. Hamby, Sandra J. Patmore, and Alan J. Kraker
- Subjects
Stereochemistry ,Antineoplastic Agents ,Mice, Inbred Strains ,Alkylation ,Alkaline hydrolysis (body disposal) ,Chemical synthesis ,Mice ,Structure-Activity Relationship ,chemistry.chemical_compound ,Morpholine ,Drug Discovery ,Tumor Cells, Cultured ,Animals ,Humans ,Urea ,Receptor, Fibroblast Growth Factor, Type 1 ,Enzyme Inhibitors ,Naphthyridines ,biology ,Bicyclic molecule ,Aryl ,Receptor Protein-Tyrosine Kinases ,Receptors, Fibroblast Growth Factor ,Xenograft Model Antitumor Assays ,chemistry ,Enzyme inhibitor ,biology.protein ,Molecular Medicine ,Drug Screening Assays, Antitumor ,Tyrosine kinase - Abstract
A series of 3-aryl-1,6-naphthyridine-2,7-diamines and related 2-ureas were prepared and evaluated as inhibitors of the FGF receptor-1 tyrosine kinase. Condensation of 4,6-diaminonicotinaldehyde and substituted phenylacetonitriles gave intermediate naphthyridine-2,7-diamines, and direct reaction of the monoanion of these (NaH/DMF) with alkyl or aryl isocyanates selectively gave the 2-ureas in varying yields (23-93%). For the preparation of more soluble 7-alkylamino-2-ureas, a number of protecting groups for the 2-amine were evaluated (phthaloyl, 4-methoxybenzyl) following selective blocking of the 7-amine (trityl), but these were not superior to the (required) 2-tert-Bu-urea group itself. Direct alkylation of the anion of the (unprotected) 7-amino group with excess 4-(3-chloropropyl)morpholine in DMF gave low (10%) yields of the desired product, but alkylation of the 7-acetamido anion, followed by mild alkaline hydrolysis, raised this to 64%. 3-Phenyl analogues were nonspecific inhibitors of isolated c-Src, FGFR, and PDGFR tyrosine kinases, whereas 3-(2,6-dichlorophenyl) analogues were most effective against c-Src and FGFR, and 3-(3,5-dimethoxyphenyl) derivatives showed high selectivity for FGFR alone. A water-soluble (7-morpholinylpropylamino) analogue retained high FGFR potency (IC(50) 31 nM) and selectivity. Pairwise comparison of the 1, 6-naphthyridines and the corresponding known pyrido[2,3-d]pyrimidine analogues showed little differences in potency or patterns of selectivity, suggesting that the 1-aza atom of the latter is not important for activity. A 7-acetamide derivative inhibited the growth of FGFR-expressing tumor cell lines and was particularly potent against HUVECs (IC(50) 4 nM). This compound was also a very potent inhibitor of HUVEC microcapillary formation (IC(50) 0.01 nM) and Matrigel invasion (IC(50) 7 nM) and showed significant in vivo antitumor effects in a highly vascularized mammary adenocarcinoma 16/c model at nontoxic doses. The compounds are worthy of further evaluation as antiangiogenesis agents.
- Published
- 2000
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