Development of novel Amadorins for Diabetic Peripheral Neuropathy

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.PROJECT NARRATIVE There is no FDA-approved disease modifying treatment for diabetic peripheral neuropathy (DPN), a condition affecting up to 50% of the estimated 30 million diabetic patients in the US. Praetego intends to advance novel, proprietary small molecule compounds believed to act on the oxidative stress pathway complicit in the pathology of DPN. We propose in Phase II comprehensive preclinical efficacy studies on the lead and back-up novel compounds that arose from our Phase I SBIR grant, using multiple rodent models of DPN, while also characterizing and optimizing their chemical properties and bioavailability.