Angiogenesis compounds inhibiting

As of today, Cediranib (AZD2171) has the potential to be a best in class angiogenesis therapy. It is one of a new generation series of orally available, highly potent inhibitors of KDR kinase. The compound inhibited VEGF-stimulated HUVEC cell proliferation with an IC50 value of 0.4 nM and was specific for this type of proliferation. 

Compounds that strongly chelate iron have been known for many years to stabilize HIF-la as well as upregulate proteins involved in red blood cell production erythropoietin (EPO), angiogenesis, vascular endothelial growth factor (VEGF), and iron transport. Some, but not all, of the pharmacological actions of iron chelators are produced by inhibition of PHD enzymes resulting in elevation of cellular HIF content. The action of selected iron chelators as they relate to PHD inhibition are briefly summarized here. 

In 2006, Jung et al. described the anti-angiogenic activity of the artemisinin monomers 52-60 using vascularized chorioallantoic membranes of chicken embryo as an in vivo model. These compounds, at concentrations as low as 5 nmol/egg, inhibited angiogenesis process by 29-75%. Monomer 60 was found to be the most effective among the tested compounds. ... 

Inhibitors of IkBo phosphorylation have been described which irreversibly inhibit cytokine-induced phosphorylation without affecting constitutive phosphorylation. One such compound (Bay 11-7083 ((E)3-[4-f-butylphenyl)-sulfonyl]-2-propenenitrile)) was found to be effective in two animal models of inflammation after intraperitoneal administration [89]. In addition to the effect it has on the expression of adhesion molecules in pro-inflammatory responses, inhibition of the transcription factor NFkB will also have an effect on angiogenesis. Endothelial cells can produce growth factors and cytokines which have pro-angiogenic effects. Some of these factors, e.g. IL-8, TNFa and MCP-1 are known to be produced via NFkB-mediated endothelial cell activation [90,91]. The importance of NFKB-mediated responses in pro-angiogenic endothelium was reflected in studies in which the NFkB inhibitor PDTC decreased retinal neovascularization in the eye of mice [92]. 

It should be noted, however, that mechanisms of action of most anti-angiogenic compounds are not well understood at present. For example, trombospondrn-1 (TSP-1) is able to inhibit tumour-associated angiogenesis, but when TSP-1 pellets were implanted into the ankles of AIA rats, it enhanced joint swelling and body weight loss in a dose- and time-dependent manner. These, possibly indirect, effects may be due to the involvement of TSP-1 in cell adhesion, as well as to its interactions with other adhesion molecules and inflammatory mediators [125]. 

Compound efficacy has been correlated with the inhibition of angiogenesis in a variety of assays (endothelial capillary tube formation, aortic ring assay, chorioallantoic membrane assay, real-time tumor blood flow and PO2 measurements, tumor blood vessel density, and tumor hypoxic and apoptotic fractions) [35]. 

Shi et al. reported on the synthesis and antiangiogenic activities of lino-mide and its analogs (compounds 11-16) [32], Three of the analogs are 3.3-69 times more potent than linomide at inhibiting blood vessel formation in the chicken chorioallantoic membrane (CAM) [41,42] angiogenesis assay. These compounds possessed considerable antiproliferative activities against isolated human umbilical vein endothelial (HUVEC) cells along with with no... 

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