Development of novel Amadorins for Diabetic Peripheral Neuropathy

The incidence of diabetes continues to increase worldwideleading to an enormous burden on health systems and the cost of health careA significant fraction of Typeanddiabetic patients will experience serious microvascular diabetic complications such as peripheral neuropathyDPNDPN patients initially experience positive sensory symptoms in the feet such as paresthesiasas well as negative symptoms such as numbnesswith progressive loss of lower extremity sensationmotor weakness results leading to loss of balancefallsulceration and lower limb amputationsCurrentlyglucose control and pain management are the backbones of treatment for diabetic neuropathyUnfortunatelypain medications offer only symptom management and do not alter the course of the diseaseFurthermorepatients with painful neuropathy often need other agents to palliate their symptomsincluding antidepressantsanticonvulsantsserotonin norepinephrine reuptake inhibitorsopiatesand topical medicationsThusa dire unmet need for interventions able to reduce or slow progression remainsPraetego Incplans to advance new chemical entitiesNCEsin the class of Amadorins for the treatment of DPN pathogenesisThough hyperglycemia is the key common factor linking all diabetic complicationsdrugs targeting the indirect pathways linked to hyperglycemia have not succeeded in clinical trialsIn contrasttwo chemically unrelated drugsaminoguanidine and pyridoxaminetargeting different chemical mechanisms to inhibit the formation of advanced glycation end productsor AGEsreached phaseclinical trials for another complicationdiabetic nephropathyOur focus in this grant is to advance drug development of new potent Amadorin AGE inhibitorsevolved from pyridoxamine by rational designthat already are showing preclinical efficacyIn this SBIR proposalwe advance the early drug development of PTGthe most potent and NCE candidate discovered so farWe focus on validating in vitro efficacy and establishing safety by comparing it to a newly designed analogue PTGWe will show that our mechanismbased SAR can successfully design novel and potent Amadorins with therapeutic potential against DPNThese objectives will be accomplished through the following aimscharacterize and compare the in vitro post Amadori inhibitory potency and anti oxidative properties of the two novel Amadorinsdevelop mass spectral analytical methods to measure the two compounds in rodent plasma samplesanddetermine the in vitro and in vivo safety profiles of the two compoundsOur findings will be critical for moving into INDenabling GLP preclinical safety and efficacy effortsComparative safety screening of potential NCEs is crucial for commercial decisions on advancing a preferred candidate through a development program Diabetic peripheral neuropathyDPNis the most common complication of typeand typediabetesaffecting approximatelyof patients over the course of their diseaseThough effective drugs are currently available to treat hyperglycemia itselfwith more under developmentHoweverthere are no approved drugs to treat the pathogenesis of diabetic complicationsIn this Phase I SBIRPraetego Incaims to develop novel therapeutic candidates to address the unmet medical need to slow the progression of DPN