Development of novel Amadorins for Diabetic Peripheral Neuropathy

项目总结 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 因足部溃疡和截肢、步态障碍和与跌倒有关的伤害而致残。没有食品和药物管理局- 批准对DPN进行疾病修正治疗，这种情况影响到约3000万人中的50% 美国的糖尿病患者。1型和2型糖尿病患者都会发生神经病变，但唯一的 目前预防或减缓神经病进展的建议是保持密切的血糖 控制力。有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，其他并发症在高级临床试验中取得了成功。Praetego Inc.计划推出新的 化学实体类“Amadorins”用于治疗DPN的发病机制。高血糖是关键 联系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末产物(AGEs)。Praetego Inc.和其他人认为年龄的形成 至少在一定程度上，这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。我们将推进领先的阿玛多林候选药物PTG的药物开发- 630，作为一项降低风险的战略，将对后备阿马多林PTG-641进行二次研究， 区别于铅的特性。在我们的第一阶段SBIR赠款中，我们研究了体外衰老抑制效力 以及最有希望的候选药物PTG-630和PTG-630的体内外安全性 PTG-640。两者都显示出预测的强大的年龄抑制作用，也都显示出希望得到改善的情况 最大耐受量(MTD)研究和体外非靶标筛查小组的安全边际。PTG-630 是最有效的抗衰老药物，被证明比我们之前的领先优势更安全。我们指定它作为我们的线索 候选人。PTG-640表现出极高的MTD，可能是由于吸收有限，在体内没有命中 体外偏离目标的面板屏幕。然而，我们首选的备份是其前体甲酯PTG-641。它被认为是 更好的候选开发药物：它应该在体内水解到安全的PTG-640，它是一个3倍的 更强的AGE抑制剂，应该有更好的生物利用度。因此，在第二阶段的STR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)将这两种导联的最佳形式推广到多种DPN啮齿动物模型的长期临床前疗效。 1型和2型糖尿病。一个关键的目标将是获得中枢神经系统和大小 转换为临床终点的纤维测量。这个项目的成功完成将决定 有足够的实验数据的两位优先候选人中的哪一位将进一步开展IND研究 为早期IND前FDA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.