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-ylidene methyl }-2,4-dimethyl-1H-pyrrol-3-yl]propionic acid) is a novel synthetic i ndolinone that potently and selectively inhibits the cellular PDGF receptor kinase and PDGF receptor-induced cell proliferation. Inhibition of PDGF re ceptor phosphorylation in cell-based assays occurs within 5 minutes after d rug exposure and persists for >6 hours after drug removal. The pharmacokine tics indicate plasma levels that exceeded the effective concentration requi red 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 bal loon arterial injury-induced stenosis model, once-daily oral or once-weekly subcutaneous administration of SU9518 reduced intimal thickening of the ca rotid 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). Thes e studies provide the rationale to evaluate PDGF receptor tyrosine kinase i nhibitors, including inhibitors related to the indolinone, SU9518, for the treatment of arterial restenosis.