Naphthamides as novel and potent vascular endothelial growth factor receptor tyrosine kinase inhibitors: design, synthesis, and evaluation.

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Harmange JC, Weiss MM, Germain J, Polverino AJ, Borg G, Bready J, Chen D, Choquette D, Coxon A, DeMelfi T, DiPietro L, Doerr N, Estrada J, Flynn J, Graceffa RF, Harriman SP, Kaufman S, La DS, Long A, Martin MW, Neervannan S, Patel VF, Potashman M, Regal K, Roveto PM, Schrag ML, Starnes C, Tasker A, Teffera Y, Wang L, White RD, Whittington DA, Zanon R

Naphthamides as novel and potent vascular endothelial growth factor receptor tyrosine kinase inhibitors: design, synthesis, and evaluation.

J Med Chem. 2008 Mar 27;51(6):1649-67. doi: 10.1021/jm701097z. Epub 2008 Mar 7.

PubMed ID

18324761 [ View in PubMed

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Abstract

A series of naphthyl-based compounds were synthesized as potential inhibitors of vascular endothelial growth factor (VEGF) receptors. Investigations of structure-activity relationships led to the identification of a series of naphthamides that are potent inhibitors of the VEGF receptor tyrosine kinase family. Numerous analogues demonstrated low nanomolar inhibition of VEGF-dependent human umbilical vein endothelial cell (HUVEC) proliferation, and of these several compounds possessed favorable pharmacokinetic (PK) profiles. In particular, compound 48 demonstrated significant antitumor efficacy against established HT29 human colon adenocarcinoma xenografts implanted in athymic mice. A full account of the preparation, structure-activity relationships, pharmacokinetic properties, and pharmacology of analogues within this series is presented.

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Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
N-cyclopropyl-6-[(6,7-dimethoxyquinolin-4-yl)oxy]naphthalene-1-carboxamide	Vascular endothelial growth factor receptor 2	IC 50 (nM)	0.6	N/A	N/A	Details