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Case Number 104010 - Compounds to Treat Cardiovascular Ischemia and promote Wound Healing

Description:  Cardiovascular ischemia is a leading cause of illness and death in the United States. A number strategies including prevention through diet, exercise and lipid-lowering drugs, and medical intervention via angioplasty, stent placement and surgery are being used to alleviate the ischemic conditions. In addition, pro-angiogenesis compounds have also been used to enhance blood flow through collateral vessel formation. However, these treatments remain inadequate because of the complications associated with these strategies. Moreover, pro-angiogenesis factors, vascular endothelial cell growth factor (VEGF) and basic fibroblast growth factor (BFGF), used to enhance blood flow in ischemic tissues have also been associated with pathological angiogenesis and/or the proliferation of tumor cells. The latter observation warrants the development of novel compounds that would specifically promote angiogenesis in ischemic tissues.
Neuropeptide Y (NPY) is a 36-residue peptide amide originally isolated from porcine brain. It is abundantly present in the sympathetic nervous system surrounding the heart and blood vessels, and also present in endothelial cells and platelets. Recent investigations using rat hind limb ischemic model, mouse corneal micro-pocket assay and chicken embryonic chorioallantoic membrane assay have unequivocally shown that NPY exhibits a powerful angiogenisis effect. Moreover, NPY has also been shown to promote wound healing, a process dependent on angiogenesis. These actions of NPY are mediated by Y2 receptor subtypes because: 1) NPY did not exhibit angiogenic activities in Y2 receptor deficient mice; 2) [Leu31, Pro34]NPY, which does not bind to Y2 receptor, had no angiogenesis effect.
It is therefore clear that NPY Y2 receptor selective agonists will ultimately be used to treat cardiovascular ischemia and promote wound healing. In this regard, we have developed highly selective and potent (Ki = 1 nM) lower molecular weight Y2-receptor agonists based on PYY(22-36) and PYY(25-36) (US Patents: 5604203 & 6046167), and shown that they exhibit to potent and prolong in vivo activities (J Med Chem 49:3420-3427; 2000; Dig Dis Sci. 44:643-648; 1999). We are now looking for partners to develop these compounds as drugs to treat cardiovascular ischemia, Peripheral arterial disease (PAD), and to promote wound healing.
Advantages
  1. Lower molecular weight compounds- will be economical to develop into drugs.
  2. Highly potent and selective- will be active at lower doses & little or no side effect expected.
  3. Relatively stable- long acting.


US Patents: 5604203 & 6046167

  • Lee et al. J Clin Invest 111:1853-1862; 2003.
  • Ekstrand et al. Proc Natl Acad Sci 100:6033-6038; 2003.
  • Zukowska-Grojec et al. Circ Res 83:187-195; 1998.
  • Zukowska et al. Trends Cardiovasc Med 13:86-92; 2003
  • Zukowska-Grojec Drug News Perspect 10: 587-595; 1997;

    For more information please contact Kellen Sensor at 513-558-5621 or Kellen.Sensor@uc.edu



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