title: The design, synthesis, and biological evaluation of potent receptor tyrosine kinase inhibitors.
abstract: Variously substituted indolin-2-ones were synthesized and evaluated for activity against KDR, Flt-1, FGFR-1 and PDGFR. Extension at the 5-position of the oxindole ring with ethyl piperidine (compound 7i) proved to be the most beneficial for attaining both biochemical and cellular potencies. Further optimization of 7i to balance biochemical and cellular potencies with favorable ADME/ PK properties led to the identification of 8h, a compound with a clean CYP profile, acceptable pharmacokinetic and toxicity profiles, and robust efficacy in multiple xenograft tumor models.
authors: Exelixis, 210 E. Grand Avenue, South San Francisco, CA 94080, USA.
authors: Moon H
authors: MH
authors: Kim
authors: Amy Lew
authors: AL
authors: Tsuhako
authors: Erick W
authors: EW
authors: Co
authors: Dana T
authors: DT
authors: Aftab
authors: Frauke
authors: F
authors: Bentzien
authors: Jason
authors: J
authors: Chen
authors: Wei
authors: W
authors: Cheng
authors: Stefan
authors: S
authors: Engst
authors: Levina
authors: L
authors: Goon
authors: Rhett R
authors: RR
authors: Klein
authors: Donna T
authors: DT
authors: Le
authors: Morrison
authors: M
authors: Mac
authors: Jason J
authors: JJ
authors: Parks
authors: Fawn
authors: F
authors: Qian
authors: Monica
authors: M
authors: Rodriquez
authors: Thomas J
authors: TJ
authors: Stout
authors: Jeffrey H
authors: JH
authors: Till
authors: Kwang-Ai
authors: KA
authors: Won
authors: Xiang
authors: X
authors: Wu
authors: F Michael
authors: FM
authors: Yakes
authors: Peiwen
authors: P
authors: Yu
authors: Wentao
authors: W
authors: Zhang
authors: Yeping
authors: Y
authors: Zhao
authors: Peter
authors: P
authors: Lamb
authors: John M
authors: JM
authors: Nuss
authors: Wei
authors: W
authors: Xu
mesh_terms: D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D015195:Drug Design; D005260:Female; D006207:Half-Life; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy; D010880:Piperidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D017434:Protein Structure, Tertiary; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
chemical_list: C576463:3-((4-chlorophenyl)(1H-imidazol-2-yl)methylene)-5-(1-ethylpiperidin-4-ylamino)indolin-2-one; D007211:Indoles; D010880:Piperidines; D047428:Protein Kinase Inhibitors; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D020794:Receptor Protein-Tyrosine Kinases