Nonpeptide Somatostatin Agonists for Retinopathy

描述(申请人提供)：糖尿病视网膜病变(DR)是美国成人失明的主要原因，其特征是异常的新生血管最终导致失明。同样，脉络膜新生血管在老年性黄斑变性(ARMD)中也可见，这是老年人失明的主要原因。目前，DR和ARMD患者都没有药物治疗，全视网膜激光凝固术是延缓失明的唯一选择。生长抑素能药物是一种生长因子抑制剂，通过阻断疾病进展中的关键中介步骤，有可能治疗糖尿病视网膜病变的可能原因。生长抑素多肽类药物在DR患者中的临床试验表明，生长抑素能药物治疗可以抑制新生血管，提高视力。然而，临床结果是高度多变的，对于接受大剂量方案或持续非肠道治疗的患者来说是最好的。这些结果与生长抑素多肽药物通过血-视网膜屏障(BRB)到达目标视网膜组织的不足是一致的。本文中描述的新型非肽亲脂性生长抑素受体激动剂具有有效穿透BRB的潜力。利用体外药理试验(第一阶段和第二阶段)和视网膜和脉络膜新生血管的动物模型(第二阶段)，本研究旨在为这类创新的化合物建立结构活性关系。最终目标是确定一种小的、有效的生长抑素能分子，它可以容易地进入目标视网膜组织，用于DR和ARMD患者的临床测试。

DESCRIPTION (provided by applicant): Diabetic retinopathy (DR), the leading cause of adult blindness in the United States, is characterized by aberrant neovascularization ultimately leading to blindness. Similarly, choroidal neovascularization is seen in age-related macular degeneration (ARMD), which is the leading cause of blindness in the elderly. Currently, there is no drug treatment for either DR or ARMD patients, with panretinal laser coagulation surgery as the only option to delay blindness. Somatostatinergic drugs are growth factor inhibitors that offer the potential to treat a probable cause of diabetic retinopathy by blocking key mediating steps in disease progression. Clinical trials with somatostatin peptide drugs in DR patients indicate that somatostatinergic drug therapy can stop neovascularization and improve visual acuity. However, the clinical results have been highly variable and have been best for patients receiving high dosage regimens or continuous parenteral treatment. These results are consistent with an inadequate blood-retinal barrier (BRB) penetration of somatostatin peptide drugs to reach target retinal tissues. New non-peptide lipophilic somatostatin receptor agonists described herein have the potential to effectively penetrate the BRB. Using pharmacological in vitro testing (Phase I and II) and animal models of retinal and choroidal neovascularization (Phase II) this study aims to establish structure activity relationships for this innovative class of compounds. The final goal is to identify a small potent somatostatinergic molecule that readily accesses target retinal tissue for clinical testing in DR and ARMD patients.