Inhibition of vascular smooth muscle cell proliferation and arterial intimal thickening by a novel antiproliferative naphthopyran

Abstract

Smooth muscle cell proliferation plays an important role in neointimal thickening after vascular injury and may contribute to restenosis after angioplasty. Development of suitable pharmacological agents modulating smooth muscle cell proliferation is critical for further investigation of vascular hyperplasia and its prevention. In the present study, we report a novel series of compounds that inhibit smooth muscle cell proliferation and arterial intimal thickening after balloon angioplasty. LY290181 (2-amino-4-[3-pyridyl]-4H-naphtho [1, 2-b]pyran-3-carbonitrile) and LY290293 (2-amino-4-[3-pyridyl]-4H-naphtho [1, 2-b]pyran-carbonitrile) produced a dose-dependent inhibition of DNA synthesis and proliferation of vascular smooth muscle cells in culture. Fifty percent inhibition (IC50) of cell proliferation was produced by 20 nM LY290181 or LY290293. Cell growth inhibition was not due to cell death, as demonstrated by the release of intracellular lactate dehydrogenase and by the reversibility of inhibition upon washing. Inhibition of smooth muscle cell proliferation was achieved in cells stimulated by either serum or individual growth factor such as platelet-derived growth factor, fibroblast growth factor or epidermal growth factor. In the rat model of balloon injury to carotid artery, LY290181 and LY290293 produced 61% (P < .005) and 48% (P < .005) inhibition of intimal thickening when administered p.o. at 100 and 120 mg/kg/day, respectively, over a 2-week period. Inhibition of intimal thickening (70%, P < .005) by LY290293 was also demonstrated when the compound was administered s.c. at 10 mg/kg/day. These studies demonstrate that naphthopyrans LY290181 and LY290293 are potent inhibitors of smooth muscle cell proliferation in vitro and that they produce substantial reduction in arterial intimal thickening in a balloon injury model when administered systemically.