title: Conformation-activity relationship on novel 4-pyridylmethylthio derivatives with antiangiogenic activity.
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, IC(50)=26nM). 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.
authors.affiliation: Research and Development Center, Santen Pharmaceutical Co. Ltd, 8916-16 Takayama-cho Ikoma-shi, Nara 630-0101, Japan. hondat@ms.naist.jp
authors.forename: Takahiro
authors.initials: T
authors.lastname: Honda
authors.forename: Hisashi
authors.initials: H
authors.lastname: Tajima
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kaneko
authors.forename: Masakazu
authors.initials: M
authors.lastname: Ban
authors.forename: Takaaki
authors.initials: T
authors.lastname: Inaba
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Takeno
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Okamoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aono
mesh_terms: D000465:Algorithms; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D020128:Inhibitory Concentration 50; D008968:Molecular Conformation; D010793:Phthalazines / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors
chemical_list: D020533:Angiogenesis Inhibitors; D010793:Phthalazines; D011725:Pyridines; D042461:Vascular Endothelial Growth Factor A; C404768:vatalanib; D040301:Vascular Endothelial Growth Factor Receptor-2