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

基本信息

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
项目类别：
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

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

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项目摘要

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.

项目摘要随着老年人的增加，包括“婴儿潮一代”的世代衰老，与年龄有关的眼睛疾病很普遍，变得越来越普遍。目前，据估计有1100万美国人受苦从与年龄相关的黄斑变性（AMD）中，这一数字预计将在下一代中翻一番。第一世界糖尿病的流行也使糖尿病病例的数量急剧增加视网膜病。在过去的几年中，FDA批准了两种抗VEGF蛋白来治疗AMD。然后成功，这些疗法很昂贵，需要定期进行玻璃体内给药。此外可以理解的患者厌恶，这些治疗具有许多不良副作用，包括结膜出血，眼痛，玻璃体漂浮物，眼内压力增加，玻璃体脱离，眼内炎症，甚至是视网膜脱离。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糖尿病性视网膜病和AMD的有效抗增殖剂。但是，像反对 VEGF蛋白质，缺乏血红视视视网膜级（BRB）穿透SST激动剂肽需要玻璃体内注射，在这种情况下使它们无吸引力。我们的I阶段方法是使用库根据我们的SBIR资助的非肽SST2A激动剂计划，用于肢端肥大和周围神经内分泌肿瘤是开发新系列SST2A激动剂的起点，能够穿透BRB和外周给药后进入后眼组织。我们将使用药理学，药用化学，物理化学特性计算，分子建模和模仿的最新体外方法 BRB的紧密连接以驱动化合物优化。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进行测试。如果成功，第二阶段将支持临床前模型中这些SST2A激动剂的测试和优化视网膜病，最初是激光诱导的脉络膜新生血管形成模型，并开始早期毒理学评估。效力将被判断为了解这些外围化合物如何与抗VEGF疗法相比。我们还将测试非肽是否可以补充蛋白质治疗剂，这种策略，如果在人类试验中出生，可以减少注射玻璃体内的数量（和伴随不良反应）由患者忍受。在第二阶段结束时，候选化合物将准备为GMP扩大毒理学实验，这将为人类的临床试验铺平道路。