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

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.

Synthesis and photocytotoxic activity of [1,2,3]triazolo[4,5-h][1,6]naphthyridines and [1,3]oxazolo[5,4-h][1,6]naphthyridines

“…[8,9] Further studies revealed that new derivatives of type 3, obtained from modification of the decoration of the lead structure at the 8-position, were endowed with significant cytotoxicity against a panel of cancer cell lines and inhibited selected oncogenic kinases. [10] FGFR-1 and VEGFR-2 kinases inhibitory activities at low nanomolar level were also exhibited by 7-acetamido [1,6]naphthyridines (4) synthetized by Thompson et al [11,12] Chart 1. Structures of [1,6]naphthyridine derivatives 1-4.…”

“…Derivatives 10 were able to generate high levels of superoxide anion and singlet oxygen, suggesting involvement of both type I and type II oxygen-dependent photosensitization mechanisms. [16] More recently we have studied pyrrolo [3',2':6,7]cyclohepta [1,2-d]pyrimidines (11) and pyrrolo [3',2':6,7]cyclohepta [1,2-b]pyridines (12) which showed very promising antitumor properties. [17,18] Upon photoactivation with light of the proper wavelength, they showed cytotoxic effect at 0.06-4.96 μM and 0.19-10.70 μM respectively, inducing apoptosis associated with rapid and massive production of large amounts of ROS, mitochondrial morphology modifications and activation of lysosomes.…”

“…Chart 2. Structures of [1,2,3]triazolo [4,5-h] [1,6]naphthyridines (5,7), [1,3]oxazolo [5,4h] [1,6]naphthyridines (6,8), pyrroloquinolines (9), pyrazoloquinolines (10), pyrrolo [3',2':6,7]cyclohepta [1,2-d]pyrimidines (11) and pyrrolo [3',2':6,7]cyclohepta [1,2b]pyridines (12).…”

Synthesis and anti-HSV-1 evaluation of new 3H-benzo[b]pyrazolo[3,4-h]-1,6-naphthyridines and 3H-pyrido[2,3-b]pyrazolo[3,4-h]-1,6-naphthyridines

“…1,6-Naphthyridines are a class of heterocyclic compounds that exhibit a broad spectrum of biological activities such as inhibitor of HIV-1 integrase [12-15], HCMV [16,17], FGF receptor-1 tyrosine kinase [18], and the enzyme acetylcholinesterase [19]. Many routes for the syntheses of 1,6-naphthyridines derivatives have previously been reported [20-24].…”

Aryl extensions of thienopyrimidinones as fibroblast growth factor receptor 1 kinase inhibitors

“…Therefore, targeted inhibition of FGFR kinases with ATP-competitive small molecule inhibitors has become an attractive therapeutic strategy. Several classes of such inhibitors of have been reported, including indolinones,5 pyrido[2,3-d]pyrimidines,6 napthyridines,7 triazines,8 indenes,9 quinolines,10 and thioindoles 11. However, only a limited number of FGFR inhibitors have entered clinical trials 12-17.…”