Nonpeptide Somatostatin Agonists for Retinopathy

描述（由申请人提供）：糖尿病视网膜病变（DR）是美国成年人失明的主要原因，其特征是异常的新生血管最终导致失明。同样，脉络膜新生血管见于年龄相关性黄斑变性（ARMD），这是老年人失明的主要原因。目前，DR或ARMD患者都没有药物治疗，全视网膜激光凝固手术是延迟失明的唯一选择。生长抑素能药物是一种生长因子抑制剂，通过阻断疾病进展的关键介导步骤，有可能治疗糖尿病视网膜病变的可能原因。生长抑素肽药物在DR患者中的临床试验表明，生长抑素能药物治疗可以阻止新生血管，改善视力。然而，临床结果变化很大，对于接受高剂量方案或持续肠外治疗的患者效果最好。这些结果与生长抑素肽药物到达目标视网膜组织的血视网膜屏障（BRB）渗透不足一致。本文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。通过体外药理学试验（一期和二期）和视网膜和脉络膜新生血管动物模型（二期），本研究旨在建立这类创新化合物的结构活性关系。最终目标是确定一个小的有效的生长抑素能分子，易于进入靶视网膜组织，用于DR和ARMD患者的临床试验。

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.