Antiangiogenic agents: an update on small molecule VEGFR inhibitors

A review. Angiogenesis is a tightly regulated process that leads to the formation of new blood vessels sprouting from pre-existing microvasculature and occurs in limited physiol. conditions or under pathol. situations such as retinopathies, arthritis, endometriosis and cancer. Blockade of angiogenesis is an attractive approach for the treatment of such diseases. Particularly in malignancies, antiangiogenic therapy should be less toxic in comparison with conventional treatments such as chemotherapy, as angiogenesis is a process relatively restricted to the growing tumor. Vascular endothelial growth factor (VEGF) is one of the most important inducers of angiogenesis and exerts its cellular effects mainly by interacting with two high-affinity transmembrane tyrosine kinase receptors: VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1). It has been proven that inhibition of VEGF receptor activity reduces angiogenesis. For these reasons, the inhibition of VEGF or its receptor signaling system is an attractive target for therapeutic intervention. The most studied and developed inhibitors are monoclonal antibodies that neutralize VEGF, ribozymes, and small mol. VEGFR kinase inhibitors. Many important reviews dealing with VEGF-induced angiogenesis and its inhibition through the block of VEGF receptors have been reported, esp. from a biol. point of view. Here, we will review small synthetic VEGFR inhibitors that have appeared in literature in the last few years, focusing our attention on their medicinal chem. in terms of chem. structure, mechanisms of action and structure-activity relationships. In fact, there have been an increased no. of tyrosine kinase inhibitors in the most recent literature reports; their biol. profile is extremely interesting and could be of great importance to medicinal chemists working in this area in improving their efficacy.