Peripheral administration of nonpeptide somatostatin agonists for ophthalmic dise

项目摘要 随着老年人口的不断增加，包括“婴儿潮一代”在内的年龄相关的眼睛 疾病很常见，而且越来越普遍。目前，估计有1100万美国人遭受 老年性黄斑变性(AMD)--这一数字预计将在下一代翻一番。 第一次世界糖尿病流行也带来了糖尿病病例的急剧上升。 视网膜病变。 在过去的几年里，FDA已经批准了两种抗血管内皮生长因子蛋白用于治疗AMD。在此期间 这些疗法很成功，费用昂贵，需要定期玻璃体内给药。除了……之外 患者的厌恶是可以理解的，这些治疗有许多副作用，包括结膜 出血、眼部疼痛、玻璃体漂浮、眼压升高、玻璃体脱离、眼内 炎症，甚至视网膜脱离。 生长抑素受体位于哺乳动物的视网膜中，早期研究表明，它们可能是 有效的抗增殖剂，用于治疗糖尿病视网膜病变和AMD等眼部疾病。然而，就像反- 血管内皮生长因子蛋白，缺乏SST激动剂多肽对血视网膜屏障(BRB)的穿透需要 玻璃体内注射，使它们在这种情况下作为药物没有吸引力。我们的第一阶段方法是使用库 来自SBIR资助的治疗肢端肥大症和外周神经内分泌的非肽SST2A激动剂计划 以肿瘤为起点开发一系列新的SST2A激动剂能够穿透BRB和 在外周给药后进入眼后部组织。我们将使用药理学、药物 化学、物理化学性质计算、分子模拟和最新的体外模拟方法 BRB的紧密连接，以推动化合物优化。我们将选择这些化合物中的一个子集 很可能会穿透BRB，并将在血浆和眼组织暴露的体内模型中对它们进行测试。 如果成功，第二阶段将支持这些SST2A激动剂在临床前模型中的测试和优化 视网膜病变，最初是激光诱导的脉络膜新生血管模型，以及开始早期 毒理学评估。疗效将被判断，以了解这些外周给药的化合物是如何 与抗血管内皮生长因子疗法相比。我们还将测试非肽是否可以补充蛋白质 治疗，一种策略，如果在人体试验中诞生，可以减少玻璃体内注射的次数(和 随之而来的不良反应)。在第二阶段结束时，候选化合物(S)将 为毒理学实验的GMP放大做好准备，这将为人类临床试验铺平道路。

Project Summary With an increasing older population, including the generational aging of the "baby boomers", age-related eye diseases are common and becoming more prevalent. Currently, it is estimated that 11 million Americans suffer from age-related macular degeneration (AMD) - a number that is expected to double in the next generation. The first world diabetes epidemic has also brought about a sharp rise in the number of cases of diabetic retinopathy. In the last few years, the FDA has approved two anti-VEGF proteins for the treatment of AMD. And while successful, these therapies are expensive and require regular intravitreal administration. In addition to understandable patient aversion, these treatments have a host of adverse side effects, including conjunctival hemorrhage, eye pain, vitreous floaters, increased intraocular pressure, vitreous detachment, intraocular inflammation, and even retinal detachment. Somatostatin receptors are located in the mammalian retina and early studies suggested they could be effective anti-proliferative agents for eye diseases such diabetic retinopathy and AMD. However, like the anti- VEGF proteins, the lack of blood-retinal-barrier (BRB) penetration by SST agonist peptides would require intravitreal injection, making them unattractive as drugs in this case. Our Phase I approach is to use the library from our SBIR-funded nonpeptide SST2A agonist program for acromegaly and peripheral neuroendrocrine tumors as a starting point to develop a new series of SST2A agonists capable of penetrating the BRB and accessing the tissues of the posterior eye after peripheral administration. We will use pharmacology, medicinal chemistry, physicochemical property calculation, molecular modeling, and the latest in vitro methods that mimic the tight junctions of the BRB to drive compound optimization. We will select a subset of these compounds that are likely to penetrate the BRB and will be test them in an in vivo model of plasma and ocular tissue exposure. If successful, Phase II will support the testing and optimization of these SST2A agonists in preclinical models of retinopathies, initally a laser-induced model of choroidal neovascularization, as well as begin early stage toxicological evaluation. Efficacy will be judged to understand how these peripherally-administered compounds compare to anti-VEGF therapies. We will also test whether the nonpeptides could complement the protein therapeutics, a strategy that if born out in human trials could diminish the number of intravitreal injections (and concomitant adverse effects) endured by patients. At the conclusion of Phase II, candidate compound(s) will be ready for GMP scale-up for toxicology experiments that will pave the way for human clinical trials.