Development of patented tricyclic pyrones molecules for the treatment of Alzheimer's Disease

Project Summary Abstract Alzheimer s diseaseADafflicts approximatelymillion people worldwide and is the most common cause of dementia in the elderlyThere is an unmet medical need for the development of new Alzheimer s disease therapeuticsAmyloidAdeposited in the Alzheimer s diseased brain has been hypothesized to initiate a cascade of molecular changes leading to synaptic dysfunctioninflammationand neuronal deathThereforedesigning therapies targeting Aand downstream events have become major strategies in Alzheimer s disease drug developmentWe have taken a rational design approach and synthesized a class of tricyclic pyrone compoundsTPsthat show potent cell protection against AtoxicityIn our completed SBIR Phase I projectthe lead compounds CPand TPwere found to have high oral bioavailabilityexcellent blood brain barrier permeabilityand low toxicityAdministering compounds orally to young Alzheimer s disease transgenic mouse models in apreventive trialresulted in substantially reduced soluble and insoluble Aspecies in the brain and preserved memory and motor functionFurthermorewe have found that the lead TPs decreased both intraneuronal and extracellular Aaggregates as well as hyperphosphorylated taup taurestored axonal traffickingand modulated hippocampal synaptic NMDA mediated activity and plasticitythese multiple synergistic cellular actionsrather than anti Atoxicity alonecould be potential mechanisms underlying their in vivo effectsIn this proposed SBIR Phase II projectour original Phase I investigative team with additional expertise in rodent brain imagingclinical Alzheimer s disease treatmentsand non GLP toxicity study providerswill conduct longitudinal studies of pharmacokinetics and pharmacodynamicsPK PDon the two aforementioned TP molecules in a new transgenic rat model of Alzheimer s diseasein order to select the best lead as the IND candidateWe now choose the new TgFAD rat model for our studies because they exhibit accumulation of oligomeric AAplaque formationTau pathologybehavioral Impairmentand neuronal loss that faithfully recapitulate hallmarks of human Alzheimer s diseaseWe will achieve our goal by accomplishing the following Specific AimsConduct PK PD studies of CPand TPon TgFAD rats using our established assays testsThe drug metabolism and PK studies include plasma and hepatocyte stabilityplasma and brain proteinbindingplasma and CSF concentrationsmetabolite identificationPinhibition inductionandexcretionIn vivo efficacy especially cognitionbrain imagingand pathologic outcomes will be examinedalong with Aand tau protein biomarkers in CSF and brain to correlate with PD outcomesPreparation for IND enabling studiesConduct pilot safety pharmacology and non GLP toxicology onthe selected therapeutic candidates through contract service organizations to help make a go no godecision for IND enabling studies in a Competing Renewal of SBIR Phase IIB or other programsExplore mechanisms of action underlying CPand TPefficacy in the transgenic rat model ofAlzheimer diseaseWe will investigate CPand TPmodulation of hippocampal synapticparticularlyNMDA receptor mediated synaptic activityplasticity and extrasynaptic NMDA receptors mediatedactivityand explore their links to other molecular and cellular actionsSuccess in Phase II will lead to an IND candidateOnce an IND application is filedit will attractnon government support and pharmaceutical partners for clinical development of this novel drug candidatefor the treatment of Alzheimer s diseasePROJECT NARRATIVE Alzheimer s disease is the major cause of dementia and one of the most disabling health conditions worldwideCurrent drugs only have modest and temporary effectsWith the growing elderly populationthere is an urgent need to develop newsafer and more effective medications for the treatment of Alzheimer s diseaseIn this SBIR Phase II projectwe propose to identify the best lead compound as a drug candidate from our two novel and patented tricyclic pyrone compounds that have shown efficacy in mouse models of Alzheimer s disease in our completed SBIR Phase I studies