Sterculic Acid Analogs to Inhibit Macular Degeneration

梧桐酸类似物抑制黄斑变性

• 批准号: 8647857
• 负责人: Alan Gordon Sutherland
• 金额: $ 22.47万
• 依托单位: L2 DIAGNOSTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8647857
• 关键词: 2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole; 7-ketocholesterol; Acids; Address; Adverse effects; Age related macular degeneration; Amides; Animal Model; Anions; Antibodies; Apoptotic; Avastin; Behavior; Biological; Biological Assay; Biological Factors; Blindness; Blood Vessels; Bruch' s basal membrane structure; Cell Line; Cells; Choroid; Choroidal Neovascularization; Chronic; Detergents; Development; Disease Progression; Dose; Drug Formulations; Drug Kinetics; Electrons; Environment; Evaluation Studies; Eye; Eyedrops; Fatty Acids; Goals; Growth; Human; Human Cell Line; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Label; Lead; Ligands; Link; Lucentis; Macular degeneration; Metabolism; Methods; Modeling; Modification; Molecular; Molecular Weight; Organ; Pathogenesis; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Pigment Epithelium; Positioning Attribute; Property; Rattus; Relative (related person); Reporting; Research Personnel; Retina; Retinal; Risk Factors; Series; Side; Small Business Innovation Research Grant; Solubility; Source; Stearoyl-CoA Desaturase; Structure; Structure of retinal pigment epithelium; Structure-Activity Relationship; Tetrazoles; Therapeutic; TimeLine; Topical application; Variant; Vertebral column; Water; age related; analog; aqueous; base; bevacizumab; carboxylate; cyclopropene; cytotoxicity; design; functional group; improved; in vitro Assay; inhibitor/antagonist; intravitreal injection; macrophage; macula; monocyte; novel; older patient; oxidation; pre-clinical; public health relevance; ranibizumab; response; retinal damage; small molecule; sterculic acid

ABSTRACT The long-term product goal of this project is a small molecule therapeutic for choroidal neovascularization (CNV, the hallmark of "wet" age-related macular degradation), an abnormal growth of blood vessels in the choroid layer of the eye that results in damage to the retina and consequent blindness. Our lead compound is the natural product sterculic acid, which has been shown to inhibit CNV in animal models. The main current treatment options for CNV involves intravitreal injection of anti-VEGF agents such as ranibizumab (Lucentis), aflibercept (Eylea) and (in off-label use) bevacizumab (Avastin) which, while often slowing disease progression, have a number of side-effects associated with the method of administration. A small molecule therapeutic which might be administered topically would present obvious advantages. Sterculic acid has very recently been shown to mitigate the induction of CNV in a rat model and to antagonize the inflammatory effects of 7- ketocholesterol (7KCh) in cultured human retinal pigment epithelium cells. However the molecule has a number of potential liabilities from the perspective of a pharmaceutically useful agent, including difficulty of isolation from natural sources, instability and lack of selectivity, which need to be addressed in parallel with a desire to also increase potency. We therefore propose to prepare analogs of sterculic acid and evaluate them in assays predictive of CNV activity and off-target selectivity. The goal of this current Phase I SBIR project is to identify analogs of sterculic acid with greater potency and improved pharmacokinetics in a range of predictive in vitro assays with minimal off-target effects. These tasks will be accomplished by carrying out a broad structure-activity relationship (SAR) study on sterculic acid - preparing a series of analogs that probe the relative importance of the existing structural features of the lead compound with a consequent optimization of activity (Aim 1) and, in parallel, preparing a further analog series which probes the pharmacokinetic space around the lead compound, utilizing analogs with water-solubilizing functionality, stabilizing groups, and acid bioisosteres resulting in improved stability, optimal logD and greater solubility (Aim 2). We will analyze the efficacy of these compounds utilizing established in vitro assays for inhibition of 7KCh-induced retinal pigmented epithelium cell inflammatory and apoptotic responses, inhibition of stearoyl CoA desaturase, and favorable pharmacokinetic properties. A successful project is expected to yield several novel inhibitors of 7KCh-induced inflammatory responses suitable for Phase II refined SAR and pharmacokinetic studies and evaluation in a rat model of CNV. We anticipate that these compounds will be potent inhibitors of CNV that can serve as leads for the development of small molecule AMD drugs with greater efficacy and preferable delivery compared to existing treatments.

抽象的 该项目的长期产品目标是用于脉络膜新生血管化的小分子治疗 （CNV，“湿”与年龄相关的黄斑降解的标志），血管异常生长 眼睛的脉络膜层会导致视网膜损害，并因此而导致失明。我们的铅院是 天然产物固化酸，已证明可以抑制动物模型中的CNV。主要电流 CNV的治疗方案涉及玻璃体内注射抗VEGF药物，例如ranibizumab（Lucentis）， Aflibercept（Eylea）和（在标签外使用）贝伐单抗（Avastin），虽然疾病的进展通常会放缓，但 具有与给药方法相关的许多副作用。小分子治疗 可以局部管理的将带来明显的优势。固化酸最近是 显示以减轻大鼠模型中CNV的诱导，并拮抗7-- 培养的人视网膜色素上皮细胞中的酮胆脂质（7kch）。但是该分子有一个 从药物有用的代理的角度来看，潜在负债的数量，包括困难 与自然来源，不稳定和缺乏选择性隔离，需要与 渴望也增加效力。因此，我们建议准备固化酸的类似物并评估它们 在预测CNV活性和脱靶选择性的测定中。 当前I阶段SBIR项目的目的是识别具有更大效力的固化酸的类似物 并在一系列预测性的体外测定中改善了药代动力学，具有最小的脱靶效应。 这些任务将通过对广泛的结构活动关系（SAR）研究来完成 固化酸 - 准备一系列类似物，以探测现有结构的相对重要性 铅化合物的特征，随之而来优化活性（AIM 1），并并行准备A 进一步的模拟系列探测铅化合物周围的药代动力学空间，利用类似物 随着水的溶解功能，稳定组和酸生物酶的稳定性提高， 最佳日志和更大的溶解度（AIM 2）。我们将分析利用这些化合物的功效 建立的体外测定法以抑制7kch诱导的视网膜色素上皮细胞炎症和 凋亡反应，抑制硬脂醇COA去饱和酶以及有利的药代动力学特性。 预计成功的项目将产生几种新型的7kch诱导炎症反应的抑制剂 适用于CNV大鼠模型中的II期精制SAR和药代动力学研究和评估。我们 预计这些化合物将是CNV的有效抑制剂，可以作为开发的铅 与现有治疗相比，具有更大疗效和可取的递送的小分子AMD药物。