Synthesis and Structure–Activity Relationships of (Aryloxy)quinazoline Ureas as Novel, Potent, and Selective Vascular Endothelial Growth Factor Receptor-2 Inhibitors

Abstract

In our continuing search for medicinal agents to treat proliferative diseases, quinazoline derivatives were synthesized and evaluated pharmacologically as epithelial growth factor receptor and vascular endothelial growth factor receptor 2 (VEGFR-2) tyrosine kinase inhibitors. A quantitative structure-activity relationship analysis was conducted to rationalize the structure-activity relationship and to predict how similar the inhibitor-binding profiles of two protein kinases are likely to be on the basis of the docking of lead coumpounds into the ATP-binding site. This model was used to direct the synthesis of new compounds. A series of N-(aromatic)-N'-{4-[(6,7-dimethoxyquinazolin-4-yl)oxy]phenyl}urea were identified as potent and selective inhibitors of the tyrosine kinase activity of VEGFR-2 (fetal liver kinase 1, kinase insert domain-containing receptor). An efficient route was developed that enabled the synthesis of a wide variety of analogues with substitution on several positions of the template. Substitution of diarylurea, competitive with ATP, afforded several analogues with low nanomolar inhibition of enzymatic activity of VEGFR-2. In this paper, we describe the synthesis, structure-activity relationships, and pharmacological characterization of the series.

Occurrence of urea-based soluble epoxide hydrolase inhibitors from the plants in the order Brassicales

“…For example, many of the kinase inhibitors, including the marketed anticancer drugs sorafenib and regorafenib, have 1, 3-disubstituted urea-based structure with antitumor activity [79]. Urea derivatives from Brassicales may interact with these target proteins.…”

Antiangiogenic compounds: well-established drugs versus emerging natural molecules

“…Although angiogenesis is a naturally occurring event, abnormal growth of new blood vessels is known to be involved in the development of various diseases including cancer, inflammation, eye illnesses, retinopathy, rheumatoid arthritis, among others [2,8]. Additionally, inadequate vessel preservation or growth may lead to ischemia causing myocardial infarction, stroke, and neurodegenerative diseases [1].…”

Discovery of biphenyl-aryl ureas as novel VEGFR-2 inhibitors. Part 4: Exploration of diverse hinge-binding fragments

“…Vascular endothelial growth factor (VEGF) and its receptors, especially VEGFR-2, are recognized as the major mediator of tumor angiogenesis. 2,3 Aberrant angiogenesis has been widely observed in many kinds of cancers including liver cancer and hepatic carcinoma. 4 Therefore, VEGFR-2 is a validated target for the discovery of novel anti-angiogenesis agents.…”