jm040099a_si_001.pdf (80.17 kB)
Synthesis and Discovery of Pyrazine−Pyridine Biheteroaryl as a Novel Series of Potent Vascular Endothelial Growth Factor Receptor-2 Inhibitors
journal contribution
posted on 2005-03-24, 00:00 authored by Gee-Hong Kuo, Aihua Wang, Stuart Emanuel, Alan DeAngelis, Rui Zhang, Peter J. Connolly, William V. Murray, Robert H. Gruninger, Jan Sechler, Angel Fuentes-Pesquera, Dana Johnson, Steven A. Middleton, Linda Jolliffe, Xin ChenPathological angiogenesis is associated with disease states such as cancer, diabetic retinopathy,
rheumatoid arthritis, endometriosis, and psoriasis. There is much evidence that direct inhibition
of the kinase activity of vascular endothelial growth factor receptor-2 (VEGFR-2) will result in
the reduction of angiogenesis and the suppression of tumor growth. Attempts to optimize a
cyclin-dependent kinase-1 (CDK1) inhibitor by using palladium-catalyzed C−C bond, C−N bond
formation reactions to assemble diverse biheteroaryl molecules led to the unexpected discovery
of a pyrazine−pyridine biheteroaryl as a novel series of potent VEGFR-2 inhibitors. Compound
15, which had IC50 = 0.084 μM at VEGFR-2, showed very modest selectivity against fibroblast
growth factor receptor-2 (IC50 = 0.21 μM), platelet-derived growth factor receptor (IC50 = 0.36
μM), and glycogen synthase kinase-3 (IC50 = 0.478 μM), while it exhibited more than 10-fold
selectivity against epidermal growth factor receptor (IC50 = 1.36 μM) and insulin-R kinase
(IC50 = 1.69 μM). On the other hand, compound 15 exhibited more than 100-fold selectivity
against calmodulin kinase 2; casein kinase-1 and -2; CDK1 and -4; mitogen-activated protein
kinase; and protein kinase A, Cβ2, and Cγ (IC50 >10 μM). Compound 15 also displayed high
inhibitory potency on VEGF-stimulated human umbilical vein endothelial cell (HUVEC)
proliferation (IC50 = 0.005 μM) and good selectivity against cell lines such as HUVEC, human
aortic smooth muscle cells, and MRC5 lung fibroblasts. Molecular docking studies were
conducted in an attempt to rationalize the unexpected high VEGFR-2 selectivity of 15.