Weekly dosing with the platelet-derived growth factor receptor tyrosine kinase inhibitor SU9518 significantly inhibits arterial stenosis.

Abstract

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.

• Authors: Y Yamasaki, K Miyoshi, N Oda, M Watanabe, H Miyake, J Chan, X Wang, L Sun, C Tang, G McMahon, K E Lipson
• Journal: Circulation research (Circ Res) Vol. 88 Issue 6 Pg. 630-6 (Mar 30 2001) ISSN: 1524-4571 [Electronic] United States
• PMID: 11282898 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Indoles
• Platelet-Derived Growth Factor
• SU9518
• PDGF receptor tyrosine kinase
• Receptors, Platelet-Derived Growth Factor

Topics

• 3T3 Cells
• Administration, Oral
• Animals
• Carotid Arteries (drug effects, pathology)
• Carotid Stenosis (pathology, prevention & control)
• Cell Division (drug effects)
• Cell Movement (drug effects)
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (blood, pharmacokinetics, pharmacology)
• Fibroblasts (cytology, drug effects, metabolism)
• Humans
• Indoles (pharmacology)
• Injections, Subcutaneous
• Kinetics
• Mice
• Muscle, Smooth, Vascular (cytology, drug effects)
• Phosphorylation (drug effects)
• Platelet-Derived Growth Factor (pharmacology)
• Rats
• Receptors, Platelet-Derived Growth Factor (antagonists & inhibitors, metabolism)
• Tunica Intima (drug effects, pathology)