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: 10079227
• 负责人: RAJA G KHALIFAH
• 金额: $ 87.44万
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10079227
• 关键词: Adopted; Advanced Development; Advanced Glycosylation End Products; Affect; Amputation; Back; Bioavailable; 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; Injury; 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; Structure; Testing; Tissues; Touch sensation; Translating; absorption; adduct; aminoguanidine; chemical property; clinically relevant; density; diabetic; diabetic patient; disability; drug candidate; drug development; efficacy study; falls; glycemic control; improved; in vivo; indexing; inhibitor/antagonist; 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.

项目摘要 糖尿病周围神经病（DPN）是最常见的糖尿病并发症。 DPN是主要原因 由于足部溃疡和截肢，收集灾难以及与跌倒有关的伤害而导致的残疾。没有FDA- 批准的DPN疾病修改治疗方法，这种疾病影响了估计3000万的50％ 美国的糖尿病患者。神经病发生在1型和2型糖尿病患者中，但唯一 当前预防或放缓神经病进展的建议是维持近距离血糖 控制。多种药物可用于治疗高血糖本身，但没有治疗DPN发病机理的药物 或其他并发症在晚期临床试验中已成功。 Praetego Inc.计划推进新的 用于治疗DPN发病机理的“ Amadorins”类的化学实体。高血糖是关键 连接所有糖尿病并发症的常见因素。蛋白质与葡萄糖的直接反应导致形成 所谓的高级糖基化终产物（年龄）。 Praetego Inc.和其他人认为年龄形成 至少部分是糖尿病的所有主要微血管并发症的基础。在糖尿病患者中，这些 葡萄糖介导的反应损害了滋养神经，视网膜和肾脏的微血管血管 glomerulli。我们目前的重点是两个新型Amadorin年龄抑制剂的临床前药物开发 在我们的I期SBIR研究中出现。我们将推进铅anmadorin候选者PTG-的药物开发 633 区分属性和铅。在我们的第一阶段SBIR赠款中，我们研究了体外年龄抑制效力 在几种新颖的anadorins，以及最有前途的候选人的体外和体内安全性，PTG-630和 PTG-640。两者都证明了预测的有效年龄抑制，也暴露了改善的希望 最大耐受剂量（MTD）研究和体外脱靶筛选面板的安全边缘。 PTG-630 是最有效的年龄抑制剂，比我们以前的潜在客户更安全。我们将其设计为我们的领导 候选人。 PTG-640表现出极高的MTD 体外脱靶面板屏幕。但是，我们首选的备份是其前体甲酯PTG-641。它被认为是 候选更好的开发药物：它应该在体内水解为安全的PTG-640，它是3倍 更强大的年龄抑制剂，它应该具有更好的生物利用度。在此II阶段，我们将：（1） 表征和优化这两种候选药物的化学特性，稳定性和生物利用度，以及 （2）将这两种导线的最佳形式推向多个DPN啮齿动物模型中的长期临床前效率 1型和2型糖尿病。关键目标将是获得中枢神经系统和大小 转化为临床终点的纤维测量。成功完成该项目将确定哪个 在两个优选的候选人中，有足够的实验数据进一步进行辅助研究 为了早期的IND FDA会议而生成。