Development of novel Amadorins for Diabetic Peripheral Neuropathy

项目摘要 糖尿病周围神经病变（DPN）是糖尿病最常见的并发症。DPN是导致 由于足部溃疡和截肢、步态障碍和跌倒相关损伤而导致的残疾。没有FDA- 批准DPN的疾病修饰治疗，这种疾病影响了估计3000万人中的50% 美国的糖尿病患者。1型糖尿病和2型糖尿病患者都有神经病变， 目前预防或减缓神经病变进展的建议是维持密切的血糖 控制多种药物可用于治疗高血糖本身，但没有治疗DPN发病机制的药物 或者其他并发症已经在高级临床试验中取得成功。Praetego Inc.计划推进新 用于治疗DPN发病机制的“Amadorins”类的化学实体。过敏是关键 所有糖尿病并发症的共同因素。蛋白质与葡萄糖的直接反应导致 所谓的晚期糖基化终产物（AGEs）。Praetego Inc.还有人认为年龄的形成 是糖尿病所有主要微血管并发症的基础。在糖尿病患者中， 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， 在我们的第一阶段SBIR研究中出现。我们将推进Amadorin的主要候选药物PTG的药物开发- 630，并且，作为降低风险的策略，将对备用Amadorin PTG-641进行二次研究， 区别于铅的特性。在我们的I期SBIR基金中，我们研究了体外AGE抑制效力， 几种新的Amadorins，以及最有前途的候选物PTG-630和 PTG-640两者都证明了预测的有效AGE抑制作用，并且还表现出希望的改善。 最大耐受剂量（MTD）研究和体外脱靶筛选组中的安全范围。公司简介 是最有效的晚期糖基化终产物抑制剂，而且比我们之前的先导药更安全。我们指定它作为我们的领导 候选人PTG-640表现出极高的MTD，可能是由于吸收有限，并且在体内没有命中。 体外脱靶组筛选。然而，我们优选的备份是其前体甲酯PTG-641。被认为 更好的候选药物开发：它应该在体内水解到安全的PTG-640，它是一个3倍 AGEs抑制剂的作用更强，生物利用度更高。因此，在本阶段II 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， (2)在多种DPN啮齿类动物模型中，将这两种药物的最佳形式推进到长期临床前疗效中 2型糖尿病的发病率一个关键的目标将是获得中枢神经系统和小型和大型 可转化为临床终点的纤维测量。这个项目的成功完成将决定 两个首选的候选人进行进一步的IND使能研究，有足够的实验数据 为IND前的FDA早期会议生成。

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.