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

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-diamino-nicotinaldehyde and substituted phenylacetoni triles gave intermediate naphthyridine-2,7-diamines, and direct reaction of the monoanion of these (NaH/DMF) with alkyl or aryl isocyanates selectivel y 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 o f the 7-amine (trityl), but these were not superior to the (required) 2-ter t-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 analogue s were nonspecific inhibitors of isolated c-Src, FGFR, and PDGFR tyrosine k inases, whereas 3-(2,6-dichlorophenyl) analogues were most effective agains t c-Src and FGFR, and 3-(3,5-dimethoxyphenyl) derivatives showed high selec tivity for FGFR alone. A water-soluble (7-morpholinylpropyl amino) analogue retained high FGFR potency (IC50 31 nM) and selectivity. Pairwise comparis on of the 1,6-naphthyridines and the corresponding known pyrido[2,3-d]pyrim idine analogues showed little differences in potency or patterns of selecti vity, suggesting that the 1-aza atom of the latter is not important for act ivity. A 7-acetamide derivative inhibited the growth of FGFR-expressing tum or cell lines and was particularly potent against HUVECs (IC50 4 nM). This compound was also a very potent inhibitor of HUVEC microcapillary formation (IC50 0.01 nM) and Matrigel invasion (IC50 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 a s antiangiogenesis agents.