10.1021/jm970367n.s001
James M. Hamby
James M.
Hamby
Cleo J. C. Connolly
Cleo J. C.
Connolly
Mel C. Schroeder
Mel C.
Schroeder
R. Thomas Winters
R. Thomas
Winters
H. D. Hollis Showalter
H.
D. Hollis Showalter
Robert L. Panek
Robert L.
Panek
Terry C. Major
Terry C.
Major
Bronislawa Olsewski
Bronislawa
Olsewski
Michael J. Ryan
Michael
J. Ryan
Tawny Dahring
Tawny
Dahring
Gina H. Lu
Gina H.
Lu
Joan Keiser
Joan
Keiser
Aneesa Amar
Aneesa
Amar
Cindy Shen
Cindy
Shen
Alan J. Kraker
Alan J.
Kraker
Veronika Slintak
Veronika
Slintak
James M. Nelson
James M.
Nelson
David W. Fry
David W.
Fry
Laura Bradford
Laura
Bradford
Hussein Hallak
Hussein
Hallak
Annette M. Doherty
Annette M.
Doherty
Structure−Activity Relationships for a Novel Series of Pyrido[2,3-<i>d</i>]pyrimidine
Tyrosine Kinase Inhibitors
American Chemical Society
1997
FGFr tyrosine kinase inhibitor 4 e
muscle cell proliferation
pyrimidine tyrosine kinase inhibitors
4 b
Compound 4 e
Compound 4 b
receptor tyrosine kinases
0.22 μ M
PD
IC 50 values
0.060 μ M
Subsequent SAR studies
ATP
50 μ M
0.3 μ M
fibroblast growth factor
Compound 6 c
InsR tyrosine kinases
compound 6 c
IC 50
pyrimidine Tyrosine Kinase Inhibitors Screening
FGFr tyrosine kinase
tyrosine kinase inhibitor
PDGFr
1997-07-18 00:00:00
Journal contribution
https://acs.figshare.com/articles/journal_contribution/Structure_Activity_Relationships_for_a_Novel_Series_of_Pyrido_2_3-_i_d_i_pyrimidine_Tyrosine_Kinase_Inhibitors/3682986
Screening 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-<i>d</i>]pyrimidine tyrosine kinase
inhibitors. The initial
lead,
1-[2-amino-6-(2,6-dichlorophenyl)pyrido[2,3-<i>d</i>]pyrimidin-7-yl]-3-<i>tert</i>-butylurea
(<b>4b</b>, PD-089828), was found to be a broadly active tyrosine kinase inhibitor.
Compound <b>4b</b> inhibited
the PDGFr, FGFr, EGFr, and c-src tyrosine kinases with IC<sub>50</sub>
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 <b>4b</b> afforded
compound <b>6c</b> with enhanced potency and bioavailability.
Compound <b>6c </b>inhibited PDGF-stimulated vascular smooth muscle cell proliferation with an
IC<sub>50</sub> of 0.3 μM. Furthermore,
replacement of the 6-(2,6-dichlorophenyl) moiety of <b>4b</b> with
a 6-(3‘,5‘-dimethoxyphenyl)
functionality produced a highly selective FGFr tyrosine kinase
inhibitor <b>4e</b>. Compound <b>4e</b>
inhibited the FGFr tyrosine kinase with an IC<sub>50</sub> of 0.060
μM, whereas IC<sub>50</sub>s for the inhibiton
of the PDGFr, FGFr, EGFr, c-src, and InsR tyrosine kinases for this
compound (<b>4e</b>) were all
greater than 50 μM.