ANGIOTENSIN ANALOGS TO TREAT WOUND HEALING

每年有800多万美国人遭受与慢性创伤相关的痛苦 糖尿病溃疡、压疮、静脉淤积性溃疡和烧伤。在……里面 许多病例的慢性伤口可能需要数年时间才能愈合，有很高的 复发率和每年54,000名患者中，导致截肢。 治疗慢性伤口的药物很少，而且没有一种是明确的 有效。Maret制药公司已经表明，血管紧张素肽 能快速有效地促进伤口愈合。他们发现了 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和更多 比任何其他已知的治疗方法都有效。A1-7没有加压装置 对动物无毒，将在临床上安全使用 在人体上进行试验。这项提议的目标是在体外培养 鉴定第二代组织再生铅的筛选试验 比A1-7更有效、更有效、更持久的化合物。 我们将开发检测血管紧张素肽结合到 天然和重组受体亚型及功能分析 测量对这些受体激活的反应。我们将测试一个 我们为亲和力而合成的大量血管紧张素类似物 以及对这些不同受体亚型的疗效。这些化合物将 也可以在衡量伤口愈合的体外筛选试验中进行测试 能力。在未来的研究中(第二阶段应用)，前景看好 在这些筛选试验中确定的化合物将在 与我们为A1-7开发的相同的临床前动物研究 可用于治疗的更有效和更长效的药物 有慢性伤口的个人。此外，筛查分析表明 在此阶段开发的SBIR提案还将允许我们在未来 研究确定非肽组织再生药物可以提供 目前与多肽药物相比有许多商业优势 可用。 建议的商业应用： 慢性创伤对人们的健康和生活方式有毁灭性的影响 每年超过800万美国人。初级药理作用 糖尿病创面愈合的治疗是生长因子PDGF (RegranexTM)，其性能比 对照，但在治疗伤口方面并不有效，原因是 压疮，伤口愈合的最大市场。Regranex是 昂贵，患者平均花费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有数百个 一年几百万美元。

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.