Vascular endothelial growth factor receptor inhibitors

Strumberg D et al (2005) Phase I clinical and pharmacokinetic study of the novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors. J Clin Oncol 23 965-972... 

Fox E et al (2010) A phase 1 trial and pharmacokinetic study of cediranib, an orally bioavail-able pan-vascular endothelial growth factor receptor inhibitor, in children and adolescents with refractory solid tumors. J Clin Oncol 28 5174-5181... 

Clark JW, Eder JP, Ryan D, et al. Safety and pharmacokinetics of the dual action Raf kinase and vascular endothelial growth factor receptor inhibitor, BAY 43-9006, in patients with advanced, refractory solid tumors. Clin Cancer Res. 2005 ll(15) 5472-5480. 

Optimization of the large (MW = 512), lipophilic (clogP = 7.6), and very potent (Kj = 0.22 nM) Vascular Endothelial Growth Factor Receptor Tyrosine Kinase (VEGFR TK) inhibitor 8 (LLE = 2.1) to produce the development candidate axitinib (9) was recently reported [17]. 

B.K., Yu, S. and Hartman, G.D. (2004) Potent N-(l,3-thiazoyl-2-yl)pyridine-2-amine vascular endothelial growth factor receptor tyrosine kinase inhibitors with excellent pharmacokinetics and low affinity for the hERG ion channel. Journal of Medicinal Chemistry, 47, 6363-6372. 

Development of Angiogenesis Inhibitors to Vascular Endothelial Growth Factor Receptor 2 for Cancer Therapy... 

Fong TAT, Shawver LK, Sun L, et al. SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-l/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types. Cancer Res 1999 59 99-106. 

Compound 57 has been identified as a vascular endothelial growth factor receptor-2 (VEGFR-2) kinase inhibitor of interest for the treatment of cancer <20030PD676>. 

Reardon DA et al (2009) Phase I pharmacokinetic study of the vascular endothelial growth factor receptor tyrosine kinase inhibitor vatalanib (PTK787) plus imatinib and hydroxyurea for malignant glioma. Cancer 115 2188-2198... 

Eskens FA et al (2006) The clinical toxicity profile of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) targeting angiogenesis inhibitors a review. Eur J Cancer 42 3127-3139... 

Wood, J. M., Bold, G., Buchdunger, E., Cozens, R., Ferrari, S., et al. 2000. PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration. Cancer Res. 60 2178-2189. 

C. Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors... 

Figure 4.10 Example of a heterogeneous SAR. Four inhibitors of vascular endothelial growth factor receptor (YEGFR-2) tyrosine kinase are shown. The two inhibitors at the top have different core structures but equally high potency and are thus part of a continuous SAR. By contrast, closely related analogs of each inhibitor shown at the bottom have several orders of magnitude lower potency, which is a characteristic feature of discontinuous SARs.

Motzer RJ, Michaelson MD, Redman BG et al (2006) Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 24 16-24... 

Mendel DB, Schreck RE, West DC, Li G, Strawn LM, et al. 2000. The angiogenesis inhibitor SU5416 has long-lasting effects on vascular endothelial growth factor receptor phosphorylation and function. Clin. Cancer Res. 6 4848-58... 

Examples of compounds in various stages of clinical development include HER2 kinase inhibitors (ZD-1839 [158], CP-358774 [159] and PD-0183805 [160)], Bcr-Abl (CGP-57148, 161) and vascular endothelial growth factor receptor kinase inhibitors (SU-5416, 162). Although many of the starting leads were obtained by random screening approaches, further medicinal chemistry was aided by the availability of a number of crystal structures and other modelling approaches. 

Note of worth is also the successful replacement of the methyl ester with oxime ethers and Af-methoxy imidoyl nitrile in the design of muscarinic agonists (Figure 15.28). Several 1,2,4-oxadiazoles and the other five-mem-bered heterocycles are employed also for other therapeutic indications like monoamine transporter and opioid receptors,5-HT agonists, bradykinin Bi receptor antagonists, and vascular endothelial growth factor receptor (VEGFR-2) inhibitors. ... 

Lombardo, L. J., Fargnoli, J., Bhide, R. S. Design, synthesis, and evaluation of orally active 4-(2,4-difluoro-5-(methoxycarbamoyl)phe nylamino)pyrrolo[2,l-f][l,2,4]triaz ines as dual vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1 inhibitors. J. Med. Chem. 2005, 4S(12), 3991-4008. 

Weng D E, Masci P A, et al. (2005). A phase I clinical trial of a ribozyme-based angiogenesis inhibitor targeting vascular endothelial growth factor receptor-1 for patients with refractory solid tumors. Mol. Cancer Ther. 4 948-955. 

Pazopanib Votrient GlaxoSmithKline 2009 Multikinase inhibitor with targets that include vascular endothelial growth factor receptors Ovarian cancer, soft tissue sarcoma 139... 

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