jm970367n_si_001.pdf (394.58 kB)
Structure−Activity Relationships for a Novel Series of Pyrido[2,3-d]pyrimidine Tyrosine Kinase Inhibitors
journal contribution
posted on 1997-07-18, 00:00 authored by James M. Hamby, Cleo J. C. Connolly, Mel C. Schroeder, R. Thomas Winters, H. D. Hollis Showalter, Robert L. Panek, Terry C. Major, Bronislawa Olsewski, Michael J. Ryan, Tawny Dahring, Gina H. Lu, Joan Keiser, Aneesa Amar, Cindy Shen, Alan J. Kraker, Veronika Slintak, James M. Nelson, David W. Fry, Laura Bradford, Hussein Hallak, Annette M. DohertyScreening of a compound library for inhibitors of the fibroblast
growth factor (FGFr) and
platelet-derived growth factor (PDGFr) receptor tyrosine kinases led to
the development of a
novel series of ATP competitive
pyrido[2,3-d]pyrimidine tyrosine kinase
inhibitors. The initial
lead,
1-[2-amino-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]-3-tert-butylurea
(4b, PD-089828), was found to be a broadly active tyrosine kinase inhibitor.
Compound 4b inhibited
the PDGFr, FGFr, EGFr, and c-src tyrosine kinases with IC50
values of 1.11, 0.13, 0.45, and
0.22 μM, respectively. Subsequent SAR studies led to the
synthesis of new analogs with
improved potency, solubility, and bioavailability relative to the
initial lead. For example, the
introduction of a [4-(diethylamino)butyl]amino side chain
into the 2-position of 4b afforded
compound 6c with enhanced potency and bioavailability.
Compound 6c inhibited PDGF-stimulated vascular smooth muscle cell proliferation with an
IC50 of 0.3 μM. Furthermore,
replacement of the 6-(2,6-dichlorophenyl) moiety of 4b with
a 6-(3‘,5‘-dimethoxyphenyl)
functionality produced a highly selective FGFr tyrosine kinase
inhibitor 4e. Compound 4e
inhibited the FGFr tyrosine kinase with an IC50 of 0.060
μM, whereas IC50s for the inhibiton
of the PDGFr, FGFr, EGFr, c-src, and InsR tyrosine kinases for this
compound (4e) were all
greater than 50 μM.
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FGFr tyrosine kinase inhibitor 4 emuscle cell proliferationpyrimidine tyrosine kinase inhibitors4 bCompound 4 eCompound 4 breceptor tyrosine kinases0.22 μ MPDIC 50 values0.060 μ MSubsequent SAR studiesATP50 μ M0.3 μ Mfibroblast growth factorCompound 6 cInsR tyrosine kinasescompound 6 cIC 50pyrimidine Tyrosine Kinase Inhibitors ScreeningFGFr tyrosine kinasetyrosine kinase inhibitorPDGFr
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