Affiliation: | aResearch and Development Center, Santen Pharmaceutical Co. Ltd, 8916-16 Takayama-cho Ikoma-shi, Nara 630-0101, Japan bGraduate School of Materials Sciences, Nara Institute of Science and Technology, 8916-5 Takayama-cho Ikoma-shi, Nara 630-0192, Japan |
Abstract: | We found 4-pyridylmethylthio derivative 1 to be very effective in using antiangiogenesis activity to prevent proliferation of HUVECs (Human Umbilical Vein Endothelial Cells), which was induced by vascular endothelial growth factor (VEGF). Compound 1 was equally effective in inhibiting VEGF receptor2 tyrosine kinase (KDR, IC50 = 26 nM). We deduced that the inhibition was the result of binding the catalytic domain of VEGF receptor2 tyrosine kinase in a similar fashion to both phthalazine derivative PTK787 2 and anthranylamide derivative AAL993 3. In this report, we will describe the conformational analyses, from ab initio MO calculation and X-ray crystallographic analyses, of compound 1 and the analogs, which include non-active 9, all in comparison with 2 and 3. The conformation–activity relationships suggest that a nonbonded intramolecular interaction between the sulfur and the carbonyl oxygen of 1 was very important in inhibiting KDR. |