Novel NMDA-targeted Therapy for Alzheimer's Disease

AbstractAlzheimer s diseaseADis a devastating form of dementia with an increasing incidence due to our aging populationWhile the FDA approved N methyl d aspartateNMDAreceptor drug memantine offers some modest beneficial effectwe have developed much improved novel aminoadamantane nitratesNitroSynapsinsthat are bifunctional NMDAR antagonists with selectivity for extra synaptic eNMDARs relative to synaptic NMDARsImportantlythis series of drugs has the potential to be a diseasemodifying intervention for AD because the lead candidate compoundYQWcan reverse synaptic loss in preclinical studies in two AD transgenic animal models and dramatically improve neurobehavior on memory testingLoss of synaptic function is associated with cognitive decline in ADIn factthe loss of synapses is a better predictor of cognitive loss in AD than plaques or tanglesTerryShengEmerging evidence suggests that oligomers of Areleasevia stimulation ofnicotinic receptorsexcessive amounts of glutamate from astrocyteswhichin turn activates eNMDARsat least in part responsible for mediating synaptic damageIn ADstimulation of eNMDARs also increases hyperphosphorylation of Tauwhich gives rise to neurofibrillary tangles and whose deposition strongly correlates with progression of ADWangAdditionallyeNMDAR mediated increases in Tau protein levelsTau hyperphosphorylationand caspaseactivity in response to oligomerized Apresage the loss of synapsesIttnerZempelHymanJinMorrisSydowD AmelioTalantovaOur lead NitroSynapsin can reverse these deficitsas shown in the Preliminary StudiesTalantovaProtection of the synapse may be achieved by eNMDAR antagonists sufficiently potent to protectyet gentle enough to allow normal synaptic transmission and neurobehavioral improvementConsidering the safety profile of memantine over many years of clinical useand the vastly improved selectivity and efficacy both in vitro and in vivo of NitroSynapsins over memantineit seems likely that the enhanced activity of our new drugs will translate into better clinical outcomes in humansIn Phase Iwe initiated clinical development of YQWcarrying out PK and brain uptake studiesmetabolic stability studies and initial toxicity studiesBased on the successful outcome of those studies we plan to initiate IND enabling studies under this Phase II SBIR applicationOur two year goal is to submit an IND to begin the clinical development of the first in class member of this novel AD modifying class of pharmaceuticalsPhase IRAG