Ribonucleotide Reductase Inhibitors for Restenosis

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Department of Health and Human Services
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Phase I
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DESCRIPTION (provided by applicant): Coronary artery disease is a major health problem and the leading cause of premature death in the US. Percutaneous coronary intervention with stenting is the primary treatment strategy for many patients with occlusive v ascular pathology; however it has been undermined by a high incidence of restenosis. The combination of stenting with drug delivery has significantly reduced restenosis rates. The two drugs delivered with stent devices that have the best reported success i n reducing restenosis are rapamycin and taxol, agents that impede smooth muscle cell migration and proliferation, critical components of restenosis injury. However, the increased incidence of thrombosis observed in a number of clinical trials examining dru g eluting stents (DES), have made thrombosis a critical issue in the use of these devices. In this regard, efforts are being pursued to develop new therapeutic compounds that confer anti-restenotic activity while reducing the pro-thrombotic effects observe d with current DES. As such, we propose that the conversion of ribonucleotides to deoxyribonucleotides is an attractive therapeutic target to control cell proliferation and will reduce restenosis because it is a rate-limiting step in the biochemical pathwa y to DNA synthesis and thus cell replication. MFH has developed novel agents to inhibit deoxynucleotide synthesis through their effect on ribonuceotide reductase (RR). Proof of concept experiments utilizing a rat model of balloon-mediated carotid injury ev aluated two MFH drugs, Didox and Imidate, and the classic RR inhibitor hydroxyurea. RR inhibition resulted in a 65% or greater decrease in the intima/media ratio at two weeks post injury with greater benefit seen at 6 weeks. In addition to the effects of t hese compounds on ribonucelotide reductase activity, Didox and Imidate have been reported to scavenge free radicals, exert robust anti-inflammatory properties and perhaps most importantly, reduce Tissue Factor expression. The effects on Tissue Factor have important therapeutic implications in limiting in-stent thrombosis, as TF has been shown to be a critical effector molecule in the pathogenesis of stent thrombosis observed with DES. On the basis of these promising results, we will assess the anti-restenot ic effects of Didox, Imidate, and hydroxyurea using animal models of vascular injury and stent deployment. In this Phase I SBIR proposal, we will examine the ability of MFH drugs to reduce restenosis following stent deployment in rat and hypercholesterolem ic rabbit models. Additionally, studies pertaining to MFH drugs' ability to prevent thrombosis are proposed. Results from these studies will determine the therapeutic potential of these compounds in the treatment of in-stent restenosis in humans. PUBLIC HE ALTH RELEVANCE Angioplasty of the heart has greatly benefited patients with occluded coronary arteries, but has been undermined by a high incidence of restenosis (vessel re-narrowing) requiring repeat angioplasty or bypass surgery. In an attempt to prevent restenosis of the vessel, drug eluting stents (DES) were developed as a mechanical/pharmaceutical solution. Although this technology has reduced the incidence of restenosis, life threatening blood clot formation within the stents has increased and thus ca lled into question the efficacy of DES. In this regard, MFH has developed compounds with potent anti-proliferative and anti-thrombotic properties that have been demonstrated to significantly reduce vessel restenosis associated with mechanical injury of the vessel wall.

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