Development of novel Amadorins for Diabetic Peripheral Neuropathy

开发治疗糖尿病周围神经病变的新型 Amadorins

• 批准号: 10461055
• 负责人: RAJA G KHALIFAH
• 金额: $ 37万
• 依托单位: PRAETEGO, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-19 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10461055
• 关键词: Adopted; Advanced Development; Advanced Glycosylation End Products; Affect; Amputation; Back; Biological; Biological Availability; Blood - brain barrier anatomy; Blood Vessels; Chemicals; Clinical; Clinical Trials; Complications of Diabetes Mellitus; Consensus; Data; Development; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Nephropathy; Disease; Dose; Esters; Exhibits; FDA approved; Fiber; Foot Ulcer; Formulation; Free Radicals; Frequencies; Functional disorder; Gait abnormality; Glucose; Grant; Guidelines; Hyperglycemia; In Vitro; Incidence; Insulin-Dependent Diabetes Mellitus; Kidney; Kidney Diseases; Kidney Glomerulus; Lead; Life; Light; Link; Maillard Reaction; Maximum Tolerated Dose; Measurement; Measures; Mediating; Microvascular Dysfunction; Modeling; Motor; Nerve; Neuraxis; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; Oxidative Stress Pathway; Pathogenesis; Pathology; Patients; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Phase; Phase III Clinical Trials; Preclinical Drug Development; Probability; Process; Property; Proteins; Pyridoxamine; Reaction; Reactive Oxygen Species; Recommendation; Retina; Retinal Diseases; Risk; Rodent Model; Safety; Sampling; Sensory; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Sodium Chloride; Testing; Tissues; Touch sensation; Translating; absorption; adduct; aminoguanidine; chemical property; clinically relevant; density; diabetic; diabetic patient; disability; drug candidate; drug development; efficacy study; fall injury; glycemic control; improved; in vivo; indexing; inhibitor; lead candidate; meetings; novel; preclinical efficacy; prevent; response; screening panel; small molecule; stability testing; stable isotope; therapeutic target

PROJECT SUMMARY Diabetic peripheral neuropathy (DPN) is the most common diabetic complication. DPN is a leading cause for disability due to foot ulceration and amputation, gait disturbance, and fall-related injury. There is no FDA- approved disease modifying treatment for DPN, a condition affecting up to 50% of the estimated 30 million diabetic patients in the US. Neuropathy occurs in patients with both type 1 and type 2 diabetes but the only current recommendation for preventing or slowing progression of neuropathy is to maintain close glycemic control. Multiple drugs are available to treat hyperglycemia itself, but no drugs that treat the pathogenesis of DPN or the other complications have succeeded in advanced clinical trials. Praetego Inc. plans to advance new chemical entities in the class of “Amadorins” for the treatment of DPN pathogenesis. Hyperglycemia is the key common factor linking all diabetic complications. Direct reaction of proteins with glucose leads to formation of so-called advanced glycation endproducts (AGEs). Praetego Inc. and others believe that AGE formation underlies, at least in part, all the major microvascular complications of diabetes. In diabetic patients, these glucose-mediated reactions damage the microvascular blood vessels that nourish nerves, the retina and kidney glomeruli. Our present focus is the preclinical drug development of two novel Amadorin AGE inhibitors that emerged in our Phase I SBIR study. We will advance the drug development of a lead Amadorin candidate, PTG- 630, and, as a de-risking strategy, secondary studies will be carried out on a back-up Amadorin PTG-641, with distinguishing properties from the lead. In our Phase I SBIR grant, we studied the in vitro AGE inhibition potency of several novel Amadorins, and the in vitro and in vivo safety of the most promising candidates, PTG-630 and PTG-640. Both demonstrated the predicted potent AGE inhibition and also exhibited the hoped for improved margin of safety in maximum tolerated dose (MTD) studies and in in vitro off-target screening panels. PTG-630 was the most potent AGE inhibitor and proved safer than our previous lead. We designate it as our lead candidate. PTG-640 demonstrated an extremely high MTD, likely due to limited absorption, and no hits in the in vitro off-target panel screen. However, our preferred back-up is its precursor methyl ester PTG-641. It is deemed the better drug candidate for development: it should hydrolyze in the body to the safe PTG-640, it is a 3-fold stronger AGE inhibitor, and it should have better bioavailability. Thus, in this Phase II STTR we will: (1) characterize and optimize the chemical properties, stability and bioavailability of these two drug candidates, and (2) advance the best forms of these two leads into long-term preclinical efficacy in multiple DPN rodent models of Type 1 and Type 2 diabetes. A key objective will be obtaining central nervous system and small and large fiber measurements that translate to clinical endpoints. Successful completion of this project will determine which of the two preferred candidates to carry further into IND-enabling studies, with sufficient experimental data generated for an early pre-IND FDA meeting.

项目概要 糖尿病周围神经病变（DPN）是最常见的糖尿病并发症。 DPN 是导致 由于足部溃疡和截肢、步态障碍以及跌倒相关损伤而导致的残疾。没有FDA—— 批准针对 DPN 的疾病修饰治疗，这种疾病影响了估计 3000 万人中高达 50% 的患者 美国的糖尿病患者。 1 型和 2 型糖尿病患者都会出现神经病变，但唯一的 目前预防或减缓神经病变进展的建议是维持接近的血糖水平 控制。有多种药物可治疗高血糖本身，但尚无治疗 DPN 发病机制的药物 或其他并发症已在高级临床试验中取得成功。 Praetego Inc. 计划推进新的 “Amadorins”类化学实体，用于治疗 DPN 发病机制。高血糖是关键 连接所有糖尿病并发症的共同因素。蛋白质与葡萄糖直接反应，形成 所谓的晚期糖基化终产物（AGE）。 Praetego Inc. 和其他公司认为 AGE 的形成 至少部分是糖尿病所有主要微血管并发症的基础。在糖尿病患者中，这些 葡萄糖介导的反应会损害滋养神经、视网膜和肾脏的微血管 肾小球。我们目前的重点是两种新型 Amadorin AGE 抑制剂的临床前药物开发， 出现在我们的第一阶段 SBIR 研究中。我们将推进 Amadorin 主要候选药物 PTG-的药物开发 630，并且作为一种降低风险的策略，将对备用 Amadorin PTG-641 进行二次研究，其中 与铅的区别特性。在我们的 I 期 SBIR 资助中，我们研究了体外 AGE 抑制效力 几种新型 Amadorins 的研究，以及最有希望的候选药物 PTG-630 和 PTG-630 的体外和体内安全性 PTG-640。两者都证明了预期的有效 AGE 抑制作用，并且还表现出了改善的希望 最大耐受剂量（MTD）研究和体外脱靶筛选组的安全边际。 PTG-630 是最有效的 AGE 抑制剂，并且被证明比我们之前的先导药物更安全。我们指定它为我们的领导者 候选人。 PTG-640 表现出极高的 MTD，可能是由于吸收有限，并且在内部没有命中 体外脱靶面板筛选。然而，我们首选的备用产品是其前体甲酯 PTG-641。则视为 更好的候选药物开发：它应该在体内水解成安全的PTG-640，它是3倍 更强的AGE抑制剂，应该具有更好的生物利用度。因此，在第二阶段 STTR 中，我们将：(1) 表征和优化这两种候选药物的化学性质、稳定性和生物利用度，以及 (2) 将这两种线索的最佳形式推进到多种 DPN 啮齿动物模型中的长期临床前疗效 1 型和 2 型糖尿病。一个关键目标是获得中枢神经系统和小型和大型 转化为临床终点的纤维测量。该项目的成功完成将决定 两个首选候选人进一步进行 IND 支持研究，并有足够的实验数据 为早期 IND 前 FDA 会议生成。