Structure-activity relationships for a novel series of pyrido[2,3-d]pyrimidine tyrosine kinase inhibitors.
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-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 microM, 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 microM. 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 microM, whereas IC50s for the inhibition of the PDGFr, FGFr, EGFr, c-src, and InsR tyrosine kinases for this compound (4e) were all greater than 50 microM.
Hamby
J M
JM
Parke-Davis Pharmaceutical Research, Division of Warner Lambert Company, Ann Arbor, Michigan 48105, USA. HambyJ@aa.wl.com
Connolly
C J
CJ
Schroeder
M C
MC
Winters
R T
RT
Showalter
H D
HD
Panek
R L
RL
Major
T C
TC
Olsewski
B
B
Ryan
M J
MJ
Dahring
T
T
Lu
G H
GH
Keiser
J
J
Amar
A
A
Shen
C
C
Kraker
A J
AJ
Slintak
V
V
Nelson
J M
JM
Fry
D W
DW
Bradford
L
L
Hallak
H
H
Doherty
A M
AM
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
D004791:Enzyme Inhibitors; C107527:PD 161570; D011743:Pyrimidines; D014508:Urea; D020794:Receptor Protein-Tyrosine Kinases