title: Distribution, metabolism, and excretion of the anti-angiogenic compound SU5416.
abstract: SU5416, 3-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-1,3-dihydro-indol-2-one, is a potent inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinase, Flk-1/KDR (fetal liver kinase 1/kinase insert domain-containing receptor), also known as VEGF receptor 2 (VEGFR2). It was the first VEGFR2 inhibitor to enter clinical trials for the treatment of colorectal and non-small cell lung cancers. Pre-clinical evaluation of SU5416 included studies related to the distribution, metabolism and excretion of this compound. These studies have provided information useful in understanding the disposition and metabolism of the indolinone class of chemicals, which has not been studied previously with therapeutic intent. The lessons we learned from SU5416 have been successfully applied in developing next generation indolinone compounds targeting tumor angiogenesis.
authors.affiliation: Portola Pharmaceuticals, 270 East Grand Ave. South San Francisco, CA 94080, USA. cye@portola.com
authors.forename: Christine
authors.initials: C
authors.lastname: Ye
authors.forename: David
authors.initials: D
authors.lastname: Sweeny
authors.forename: Juthamas
authors.initials: J
authors.lastname: Sukbuntherng
authors.forename: Qingling
authors.initials: Q
authors.lastname: Zhang
authors.forename: Weiwei
authors.initials: W
authors.lastname: Tan
authors.forename: Simon
authors.initials: S
authors.lastname: Wong
authors.forename: Ajay
authors.initials: A
authors.lastname: Madan
authors.forename: Brian
authors.initials: B
authors.lastname: Ogilvie
authors.forename: Andrew
authors.initials: A
authors.lastname: Parkinson
authors.forename: Lida
authors.initials: L
authors.lastname: Antonian
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000818:Animals; D001345:Autoradiography; D001711:Biotransformation; D001798:Blood Proteins / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D011485:Protein Binding; D011758:Pyrroles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013045:Species Specificity
chemical_list: D020533:Angiogenesis Inhibitors; D001798:Blood Proteins; D007211:Indoles; D011758:Pyrroles; C116890:Semaxinib; D003577:Cytochrome P-450 Enzyme System