The design, synthesis, and biological evaluation of potent receptor tyrosine kinase inhibitors |
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| Authors: | Moon H Kim Amy Lew Tsuhako Erick W Co Dana T Aftab Frauke Bentzien Jason Chen Wei Cheng Stefan Engst Levina Goon Rhett R Klein Donna T Le Morrison Mac Jason J Parks Fawn Qian Monica Rodriquez Thomas J Stout Jeffrey H Till Kwang-Ai Won Xiang Wu F Michael Yakes Peiwen Yu Wentao Zhang Yeping Zhao Peter Lamb John M Nuss Wei Xu |
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| Institution: | Exelixis, 210 E. Grand Avenue, South San Francisco, CA 94080, USA. |
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| 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. |
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