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脉络膜新生血管的小分子治疗药物 （CNV，“湿性”年龄相关性黄斑退化的标志），血管异常生长 眼睛脉络膜层，导致视网膜损伤并随后失明。我们的先导化合物是 天然产物梧桐酸，在动物模型中已被证明可以抑制 CNV。主电流 CNV 的治疗方案包括玻璃体内注射抗 VEGF 药物，例如雷珠单抗 (Lucentis)、 阿柏西普 (Eylea) 和（超说明书使用）贝伐单抗 (Avastin)，虽然通常可以减缓疾病进展， 具有许多与给药方法相关的副作用。小分子疗法 局部给药将带来明显的优势。梧桐酸最近被 显示可减轻大鼠模型中 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固醇 (7KCh)。然而该分子有一个 从药学上有用的试剂的角度来看，潜在的责任数量，包括困难 与自然资源隔绝、不稳定和缺乏选择性，这些问题需要与 也希望增加效力。因此，我们建议制备梧桐酸类似物并对其进行评估 用于预测 CNV 活性和脱靶选择性的检测。 当前第一阶段 SBIR 项目的目标是鉴定具有更强效力的梧桐酸类似物 并在一系列预测性体外测定中改进了药代动力学，并且脱靶效应最小。 这些任务将通过开展广泛的结构-活性关系（SAR）研究来完成 梧桐酸 - 制备一系列类似物，以探究现有结构的相对重要性 先导化合物的特征以及随后的活性优化（目标 1），同时制备 进一步的类似物系列，利用类似物探测先导化合物周围的药代动力学空间 具有水溶性功能、稳定基团和酸性生物等排体，从而提高稳定性， 最佳 logD 和更高的溶解度（目标 2）。我们将利用以下方法分析这些化合物的功效 建立了抑制 7KCh 诱导的视网膜色素上皮细胞炎症和 细胞凋亡反应、硬脂酰辅酶A去饱和酶的抑制以及有利的药代动力学特性。 一个成功的项目预计将产生几种 7KCh 诱导炎症反应的新型抑制剂 适用于 CNV 大鼠模型的 II 期精制 S​​AR 和药代动力学研究和评估。我们 预计这些化合物将成为 CNV 的有效抑制剂，可作为开发 与现有治疗方法相比，小分子 AMD 药物具有更高的功效和更好的递送效果。