A first-in-class orally active anti-TNF-alpha inhibitor to treat AD

ABSTRACT The goal of this proposal is to develop tumor necrosis factorTNFinhibiting compounds as neuroprotectant drugs for treating Alzheimer s diseaseADCurrent FDA approved AD interventions are symptomatic treatments with limited efficacy which do not affect AD etiology or modify the course of disease progressionThusa critical need exists for a novel AD treatment directed towards AD pathophysiologyRecent studies implicate the neuroinflammatory cytokine TNFas a key mediator in ADassociated neurodegenerative pathologyMultiple preclinical and clinical studies indicate that TNFis adruggablemolecular target to modify the course of AD progressionPreliminary Studies demonstrate that our lead compound shows potent TNFinhibition in vitroOur PhaseSBIR studies demonstrate that our small molecule TNFinhibitor administered orally or peripherally significantly improved cognitive function in multiple AD mouse modelsOur compound also modulated brain TNFprotein levelsmicroglial activationand the progress of AD associated neuropathologyNo morbiditymortality or any obvious side effects were observed despite long term oral daily treatment regimen with our compoundTaken togetherthese data strongly suggest that our lead compound is an excellent anti AD drug candidateThe proposed SBIR phasegrant studies will de risk further development of our compound byfinding a new synthetic method that is viable for commercial manufacturing andperforming key early safety toxicology studies in preparation for future FDA required IND enabling studies PROJECT NARRATIVE Alzheimer s DiseaseADis a significant neurological problem affecting nearlymillion of our senior U ScitizensThe present research aims to develop a compound that targets the underlying neuroinflammation in AD to modify disease progression and improve cognitive function