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(Circulation Research. 2001;88:630.)
© 2001 American Heart Association, Inc.

Molecular Medicine

Weekly Dosing With the Platelet-Derived Growth Factor Receptor Tyrosine Kinase Inhibitor SU9518 Significantly Inhibits Arterial Stenosis

Yasundo Yamasaki, Kazuhisa Miyoshi, Nobuyuki Oda, Motomu Watanabe, Hidekazu Miyake, Julie Chan, Xueyan Wang, Li Sun, Cho Tang, Gerald McMahon, Kenneth E. Lipson

From Taiho Pharmaceutical Co, Ltd (Y.Y., K.M., N.O., M.W., H.M.), Hanno Research Center, Saitama, Japan, and SUGEN, Inc (J.C., X.W., L.S., C.T., G.M., K.E.L.), South San Francisco, Calif.

Correspondence to Kenneth E. Lipson, SUGEN, Inc, 230 East Grand Ave, South San Francisco, CA 94080. E-mail ken-lipson{at}sugen.com

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.

Key Words: angioplasty • platelet-derived growth factor • restenosis • tyrosine kinase • indolinone

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