ANGIOTENSIN ANALOGS TO TREAT WOUND HEALING

每年有超过800万美国人患有慢性创伤， 糖尿病溃疡、压疮、静脉淤滞性溃疡和烧伤。在 在许多情况下，慢性伤口可能需要数年才能愈合， 复发率和每年54，000名患者，导致截肢。 治疗慢性伤口的药物很少，而且没有一种药物是明确的。 有效Maret Pharmaceuticals已经证明血管紧张素肽 能快速有效地促进伤口愈合。他们已经找到 血管紧张素II（AII）和血管紧张素（1-7）（A1-7）促进组织 在许多动物模型中再生更快， 比任何其他已知的治疗方法都有效。A1-7没有加压器 效果，对动物无毒，将进行临床安全性试验 人体试验本提案的目的是在体外开发 鉴定第二代组织再生铅的筛选试验 这些化合物比A1-7更有效、更有效、作用时间更长。 我们将开发测定血管紧张素肽结合的方法， 天然和重组受体亚型和功能测定 测量对这些受体激活的反应。我们将测试 我们已经合成了大量的血管紧张素类似物， 以及对这些不同受体亚型的功效。这些化合物将 还可以通过测量伤口愈合的体外筛选试验进行测试 能力的在未来的研究（第二阶段应用）中， 在这些筛选试验中鉴定的化合物将在 与我们用于A1-7开发的相同的临床前动物研究 更有效、更长效的药物， 慢性创伤患者。此外，筛选试验 在第一阶段SBIR提案中开发的技术也将使我们在未来 研究确定非肽组织再生药物， 与目前的肽类药物相比 available. 拟议的商业应用： 慢性创伤对患者的健康和生活方式具有破坏性影响， 超过800万美国人。主要药理学 治疗糖尿病伤口愈合的生长因子是PDGF （RegranexTM），其表现出比 没有发现有效治疗伤口， 压力性溃疡是伤口愈合的最大市场。雷格拉内克斯群岛 昂贵，平均花费患者2,000美元，总销售额超过 1999年，因其有限的治疗适应症而获得8000万美元。我们 预计我们的血管紧张素类似物的市场将达到数百个 一年数百万美元。

Over 8 million Americans a year suffer from chronic wounds associated with diabetic ulcers, pressure ulcers, venous stasis ulcers and burns. In many cases the chronic wounds can take years to heal, have a high recurrence rate and for 54,000 patients a year, result in amputations. There are few medications for chronic wounds and none are clearly effective. Maret Pharmaceuticals has shown that angiotensin peptides can rapidly and effectively promote wound healing. They have found that angiotensin II (AII) and angiotensin (1-7) (A1-7) promote tissue regeneration in a number of animal models quicker and more effectively than any other known treatment. A1-7 does not have pressor effects, is non-toxic to animals and will be undergoing clinical safety trials in humans. The objective of this proposal is to develop in vitro screening assays to identify second generation tissue regenerative lead compounds that are more potent, effective and longer acting than A1-7. We will develop assays to measure angiotensin peptide binding to native and recombinant receptors subtypes and functional assays measuring responses to activation of these receptors. We will test a large number of angiotensin analogs we have synthesized for affinity and efficacy at these different receptor subtypes. These compounds will also be tested on in vitro screening assays that measure wound healing capabilities. In future studies (phase II application), promising lead compounds identified in these screening assays will be tested in the same pre-clinical animals studies as we have used for A1-7 to develop more effective and longer acting drugs that can be used to treat individuals with chronic wounds. Furthermore, the screening assays developed in this phase I SBIR proposal will also allow us in future studies to identify non-peptide tissue regenerative drugs that can offer many commercial advantages over the peptide drugs presently available. PROPOSED COMMERCIAL APPLICATIONS: Chronic wounds have a devastating effect on the health and life style of over 8 million Americans a year. The primary pharmacological treatment of diabetic wound healing is the growth factor PDGF (RegranexTM) which was shown to have a 10% improvement over controls and not found to be effective in treating wounds due to pressure ulcers, the largest market for wound healing. Regranex is expensive, costing patients on average $2,000, with total sales of over $80 million in 1999 for its limited therapeutic indications. We anticipate that the market for our angiotensin analogs will be hundreds of millions of dollars a year.