Peripheral administration of nonpeptide somatostatin agonists for ophthalmic dise

非肽生长抑素激动剂的外周给药治疗眼科疾病

• 批准号: 8646108
• 负责人: Stephen F Betz
• 金额: $ 22.41万
• 依托单位: CRINETICS PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8646108
• 关键词: Acromegaly; Adverse effects; Age related macular degeneration; Aging; Agonist; American; Animal Model; Antibodies; Aqueous Humor; Biological Assay; Blood-Retinal Barrier; Cells; Choroid; Choroidal Neovascularization; Clinical Trials; Coculture Techniques; Complement; Conjunctival Hemorrhage; Diabetes Mellitus; Diabetic Retinopathy; Disease; Dose; Drug Kinetics; Drug or chemical Tissue Distribution; Epidemic; Evaluation; Eye; Eye diseases; Funding; G Protein-Coupled Receptor Genes; Goals; Government; Growth; Guidelines; Hand; Hormones; Human; In Vitro; Inflammation; Lasers; Lead; Libraries; Macular degeneration; Methods; Modeling; Molecular Models; Neuropeptides; Older Population; Oryctolagus cuniculus; Patients; Penetration; Peptides; Peripheral; Permeability; Persons; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Physiologic Intraocular Pressure; Plasma; Posterior eyeball segment structure; Pre-Clinical Model; Property; Proteins; Receptor Activation; Retina; Retinal Detachment; Retinal Diseases; Series; Small Business Innovation Research Grant; Somatostatin; Somatostatin Receptor; Staging; Testing; Therapeutic; Tight Junctions; Tissues; Toxicology; Vitreous Detachment; Vitreous humor; Work; age related; bevacizumab; design; fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether; in vitro Assay; in vivo; in vivo Model; innovation; intravitreal injection; molecular modeling; next generation; novel; novel therapeutics; ocular pain; pharmacokinetic model; pre-clinical; programs; public health relevance; receptor; research clinical testing; research study; scale up; success; tumor; vitreous floater

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.

项目概要 随着人口老龄化，包括“婴儿潮一代”的老龄化，与年龄相关的眼睛 疾病很常见并且变得越来越普遍。目前，估计有 1100 万美国人遭受苦难 年龄相关性黄斑变性（AMD）——这一数字预计在下一代会增加一倍。 第一次世界糖尿病流行也带来了糖尿病病例数的急剧上升 视网膜病变。 过去几年，FDA 批准了两种抗 VEGF 蛋白用于治疗 AMD。而同时 虽然这些疗法取得了成功，但价格昂贵并且需要定期玻璃体内给药。此外 患者的厌恶情绪是可以理解的，这些治疗有许多不良副作用，包括结膜损伤 出血、眼痛、玻璃体飞蚊症、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视网膜中，早期研究表明它们可能是 治疗糖尿病视网膜病变和 AMD 等眼部疾病的有效抗增殖剂。然而，就像反 VEGF 蛋白，SST 激动剂肽缺乏血视网膜屏障 (BRB) 渗透，需要 玻璃体内注射，使得它们在这种情况下作为药物没有吸引力。我们第一阶段的方法是使用图书馆 来自我们 SBIR 资助的用于肢端肥大症和周围神经内分泌的非肽 SST2A 激动剂项目 以肿瘤为起点开发一系列能够穿透 BRB 的新 SST2A 激动剂 外周给药后进入眼后组织。我们将利用药理学、医学 化学、理化性质计算、分子建模以及模拟的最新体外方法 BRB 的紧密连接可驱动化合物优化。我们将选择这些化合物的子集 可能会穿透 BRB，并将在血浆和眼组织暴露的体内模型中对其进行测试。 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，并开始早期阶段 毒理学评价。将判断疗效以了解这些外周给药的化合物如何 与抗 VEGF 疗法相比。我们还将测试非肽是否可以补充蛋白质 疗法，这种策略如果在人体试验中得到证实，可以减少玻璃体内注射的次数（以及 患者所忍受的伴随不良反应）。在第二阶段结束时，候选化合物将 为毒理学实验的 GMP 规模扩大做好准备，这将为人体临床试验铺平道路。