Advancing CAP4196 into in vivo Proof of Concept Translational Studies

将 CAP4196 推进体内概念验证转化研究

• 批准号: 9909237
• 负责人: Sridhar G Prasad
• 金额: $ 66.29万
• 依托单位: PLEX PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9909237
• 关键词: Address; Adopted; Africa; Aging; Anatomy; Area; Back; Bilateral; Biological Availability; Blindness; Canis familiaris; Caring; Cataract; Cataract Extraction; Chemicals; Complex; Control Groups; Corneal edema; Crystalline Lens; Crystallins; Cyclic GMP; Data; Developed Countries; Development; Diabetes Mellitus; Disease; Dose; Drug Kinetics; Endophthalmitis; Enzymes; Eye; Eyedrops; FDA approved; Family; Family suidae; Far East; Formulation; Generations; Goals; Half-Life; Heat shock proteins; Human; Intellectual Property; Intraocular lens implant device; Keratoplasty; Kilogram; Lasers; Lead; Maximum Tolerated Dose; Medical; Modeling; Molecular Chaperones; Naphthalene; New Zealand; Operative Surgical Procedures; Oral; Organ Culture Techniques; Oryctolagus cuniculus; Parkinson Disease; Pathology; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Physiological; Pre-Clinical Model; Prevention; Prodrugs; Proteins; Public Health; Recombinants; Retinal Detachment; Risk Factors; Safety; Series; Small Business Innovation Research Grant; Smoking; Solubility; Source; Time; Topical application; Trauma; Ultraviolet Rays; Uveitis; Visual impairment; World Health Organization; absorption; age related; aged; alpha-Crystallins; analog; aqueous; arm; base; blind; clinical development; cost effective; design; disparity reduction; effective intervention; effective therapy; experimental study; gamma-Crystallins; improved; in vivo; innovation; inorganic phosphate; lead candidate; lead optimization; lens; lens capsule; lens transparency; light scattering; low and middle-income countries; member; novel; phase 1 study; preclinical development; prevent; primary endpoint; programs; scaffold; secondary endpoint; small molecule; symptom treatment; tolcapone; translational study

Project Summary Cataract, the clouding of the eye lens is responsible for 51% of world blindness. According to World Health Organization nearly 18 million people are bilaterally blind from cataracts in the world. Cataract is easily treated by surgery and is considered as one of the most cost-effective interventions. Although cataract surgery is generally considered to be safe, there are significant complications: (i) 30-50% of patients in the US having cataract surgery develop opacification of the posterior lens capsule within two years and require laser treatment; (ii) 0.8% have retinal detachments; (iii) 0.6-1.3% are hospitalized for corneal edema or require corneal transplantation and (iv) about 1% are presented with endophthalmitis. In addition, in many remote and poor areas of the developing and under-developed regions of the world, people still remain blind from cataracts, primarily due to lack of access to eye care. As a result of which, cataract related blindness is as high as 50% or more in poor and remote regions of the world compared to only 5% in developed countries. Alpha-crystallin (AC) is one of the three major eye lens crystallins and is a representative member of the small heat shock protein (sHsp) family. AC serves as molecular chaperone, protecting damaged or aged lens proteins and enzymes from aggregation that would otherwise lead to light scattering and cataract formation. It is well established that chaperone-like activity (CLA) of AC is critical for lens transparency and it is hypothesized that maintaining optimal or increasing chaperone activity might aid in the prevention or slowing of cataracts. The rationale of our proposal is based on the observation that small molecule pharmacological agents from natural sources can prevent the loss of CLA of Alpha crystallin A-chain (AAC) and can delay cataract formation in preclinical models. It has been estimated that delaying cataracts formation by 10 years can reduce the vision care expense by 50%. In addition, our preliminary data supports the hypothesis that an FDA approved drug, tolcapone (CAP1160) increases AAC CLA and maintains transparency of the eye lens in organ culture experiments of cataract model. Therefore, the goal of our proposal is to advance the prodrug of CAP1160, CAP4196 through in vivo efficacy and proof of concept studies to develop a cost-effective non-surgical treatment to: (i) delay the need for cataract surgery and (ii) reduce the disparity of cataract-related blindness globally, and the specific aims are: Aim 1a. Design and synthesis of prodrugs of CAP1160, formulation, stability and maximum tolerated dose (MTD). Aim 1b. Establish cGMP manufacturing and formulation of lead candidate prodrug CAP4196. Aim 2a. Ocular pharmacokinetics of CAP4196. Aim 2b. In vivo POC and efficacy of CAP4196 in dogs with age-related cataracts. Aim 3. SAR based hit-to-lead optimization of naphthalene series from ex vivo efficacy through in vivo safety. Project milestone: Successful completion of these aims will enable CAP4196 to be advanced into clinical development.

项目摘要 白内障，眼镜镜的阴影造成51％的世界失明。根据世界 卫生组织有近1800万人双侧对世界的白内障造成了盲。白内障很容易 通过手术治疗，被认为是最具成本效益的干预措施之一。虽然白内障手术 通常认为是安全的，存在重大并发症：（i）30-50％的美国患者患有 白内障手术在两年内导致后晶状体囊的不透气，需要激光 治疗; （ii）0.8％的视网膜脱离； （iii）0.6-1.3％的角膜水肿住院或需要 角膜移植和（iv）约1％带有内嗜性。另外，在许多遥控器中 世界发展中和发达地区的贫困地区，人们仍然对白内障蒙蔽， 主要是由于无法获得眼保健。结果，白内障相关的失明高达50％或 在世界上贫穷和偏远地区，发达国家只有5％。 α-晶状体 （AC）是三个主要的眼镜结晶蛋白之一，是小热冲击的代表成员 蛋白质（SHSP）家族。 AC用作分子伴侣，可保护受损或老化的晶状体蛋白和 聚集的酶，否则会导致光散射和白内障形成。很好 确定AC的伴侣样活性（CLA）对于透镜透明度至关重要，可以假设是 保持最佳或增加的伴侣活性可能有助于预防或减慢白内障。这 我们提案的基本原理是基于这样的观察结果，即天然的小分子药理剂 来源可以防止alpha晶体A链（AAC）的CLA损失，并可以延迟白内障的形成 临床前模型。据估计，将白内障形成延迟10年可以降低视力 护理费用增加50％。此外，我们的初步数据支持以下假设：FDA批准的药物， Tolcapone（CAP1160）增加了AAC CLA并保持器官培养中眼镜的透明度 白内障模型的实验。因此，我们建议的目标是推进CAP1160的前药， CAP4196通过体内功效和概念研究证明，开发出具有成本效益的非手术性 治疗：（i）延迟白内障手术的需求，（ii）减少白内障相关失明的差异 在全球范围内，具体目的是：目标1a。 CAP1160的前药的设计和合成，配方， 稳定性和最大耐受剂量（MTD）。目标1B。建立CGMP制造和铅的配方 候选前药CAP4196。目标2a。 CAP4196的眼部药代动力学。目标2B。体内POC和功效 与年龄相关白内障的狗的CAP4196。 AIM 3。萘的基于SAR的命中率优化 从体内安全性通过体内安全性的序列。项目里程碑：这些目标的成功完成将 使CAP4196能够进入临床开发。