Weekly dosing with the platelet-derived growth factor receptor tyrosine kinase inhibitor SU9518 significantly inhibits arterial stenosis.
The platelet-derived growth factor (PDGF) ligands and their receptors have been implicated as critical regulators of the formation of arterial lesions after tissue injury. SU9518 (3[5-(5-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrol-3-yl]propionic acid) is a novel synthetic indolinone that potently and selectively inhibits the cellular PDGF receptor kinase and PDGF receptor-induced cell proliferation. Inhibition of PDGF receptor phosphorylation in cell-based assays occurs within 5 minutes after drug exposure and persists for >6 hours after drug removal. The pharmacokinetics indicate plasma levels that exceeded the effective concentration required to inhibit the PDGF receptor in cells for up to 8 hours or 7 days after a single oral or subcutaneous administration, respectively. In the rat balloon arterial injury-induced stenosis model, once-daily oral or once-weekly subcutaneous administration of SU9518 reduced intimal thickening of the carotid artery (ratio of neointimal to medial area, 1.94+/-0.38 versus 1.03+/-0.29 [P<0.01] 2.21+/-0.32 versus 1.34+/-0.45 [P<0.01], respectively). These studies provide the rationale to evaluate PDGF receptor tyrosine kinase inhibitors, including inhibitors related to the indolinone, SU9518, for the treatment of arterial restenosis.
Yamasaki
Y
Y
Taiho Pharmaceutical Co, Ltd, Hanno Research Center, Saitama, Japan.
Miyoshi
K
K
Oda
N
N
Watanabe
M
M
Miyake
H
H
Chan
J
J
Wang
X
X
Sun
L
L
Tang
C
C
McMahon
G
G
Lipson
K E
KE
D016475:3T3 Cells; D000284:Administration, Oral; D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects / Q000473:pathology; D016893:Carotid Stenosis / Q000473:pathology / Q000517:prevention & control*; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007279:Injections, Subcutaneous; D007700:Kinetics; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D051381:Rats; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology
D004791:Enzyme Inhibitors; D007211:Indoles; D010982:Platelet-Derived Growth Factor; C425884:SU9518; C099852:PDGF receptor tyrosine kinase; D017479:Receptors, Platelet-Derived Growth Factor