title: Discovery of 5-[5-fluoro-2-oxo-1,2- dihydroindol-(3Z)-ylidenemethyl]-2,4- dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide, a novel tyrosine kinase inhibitor targeting vascular endothelial and platelet-derived growth factor receptor tyrosine kinase.
abstract: To improve the antitumor properties and optimize the pharmaceutical properties including solubility and protein binding of indolin-2-ones, a number of different basic and weakly basic analogues were designed and synthesized. 5-[5-Fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (12b or SU11248) has been found to show the best overall profile in terms of potency for the VEGF-R2 and PDGF-Rbeta tyrosine kinase at biochemical and cellular levels, solubility, protein binding, and bioavailability. 12b is currently in phase I clinical trials for the treatment of cancers.
authors.affiliation: SUGEN, Inc., 230 E. Grand Avenue, South San Francisco, California 94080, USA. connie-sun@sugen.com
authors.forename: Li
authors.initials: L
authors.lastname: Sun
authors.forename: Chris
authors.initials: C
authors.lastname: Liang
authors.forename: Sheri
authors.initials: S
authors.lastname: Shirazian
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhou
authors.forename: Todd
authors.initials: T
authors.lastname: Miller
authors.forename: Jean
authors.initials: J
authors.lastname: Cui
authors.forename: Juri Y
authors.initials: JY
authors.lastname: Fukuda
authors.forename: Ji-Yu
authors.initials: JY
authors.lastname: Chu
authors.forename: Asaad
authors.initials: A
authors.lastname: Nematalla
authors.forename: Xueyan
authors.initials: X
authors.lastname: Wang
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.forename: Anand
authors.initials: A
authors.lastname: Sistla
authors.forename: Tony C
authors.initials: TC
authors.lastname: Luu
authors.forename: Flora
authors.initials: F
authors.lastname: Tang
authors.forename: James
authors.initials: J
authors.lastname: Wei
authors.forename: Cho
authors.initials: C
authors.lastname: Tang
mesh_terms: D016475:3T3 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry; D001682:Biological Availability; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors*; D012995:Solubility; D013329:Structure-Activity Relationship; D000077210:Sunitinib; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007211:Indoles; D011758:Pyrroles; D020797:Receptor, Platelet-Derived Growth Factor beta; D040301:Vascular Endothelial Growth Factor Receptor-2; D000077210:Sunitinib