Small molecule therapeutics for Alzheimer's Disease

SMALL MOLECULE THERAPEUTICS FOR ALZHEIMERandapos S DISEASE SUMMARYAlzheimerandapos s diseaseADis a progressive and fatal neurological disorder that affects approximately onetenth of the population over the age ofThere is currently no cure for the diseaseThe pathological hallmarks of the disease include the formation and accumulation in the brain ofamyloidAwidely recognized to be the major neurotoxic agent in AD and therapeutic targetCenna has a novel technology that does not target theorsecretaseswhich has yielded peptide drug candidates Pand Pwith the ability to inhibit the production of Ain vitro and in a Tg mouse model of ADPand Pgive a strongspecific and biologically relevant binding with the purified ectodomain of human APPPis at preclinical stage in its developemnt as a drug candidates for the treatment of ADIt would be a distinct advantage to identify small molecule compounds that can reduce Aby the same mechanism as the peptidesby binding APP at the same sites as Pand PThese small molecule candidates may be developed as oral drugs that can cross the BBBDuring the Phasefunding period we carried out molecular modeling studies to predict binding sites on APP for both Pand PHaving accomplished thatwe virtually screened a library of ecompounds to identify those molecules that would be predicted to bind the same sites on APP as Pand POf thestructures screeneda total ofsuggested binding to APP at either the Por Pbinding siteOf thosewe were able to successfully discover several candidates that could reduce both Aandbyin an AD patient derived induced pluripotent stem cellipscassayIn this Phaseapplication we propose to develop the best three compoundsAAand Afurther as possible orally available diseasemodifying small molecule drug candidates for the treatment of ADthat function with the same mechanism as our peptide candidatesOur Specific Aims areto carry out the synthesis and evaluation in early ADME and PharmacokineticPKproperties of compounds AAto design and synthesize novel analogs of compounds AAand to evaluate their early ADME and PK properties and their ability to reduce Ain the AD ipsc cell based assay andto study the pharmacology efficacy of selected compounds in a transgenic mouse model of Alzheimerandapos s disease Narrative Alzheimerandapos s diseaseADis a devastating degenerative neurological disorder that affects one tenth of the population over the age ofThere is no cure for the diseaseWe have discovered small molecule compoundsbased on the mechanism of action of our peptide drug candidates Pand Pthat are under developmentThese compounds can reduce the toxic species Ain a cell based assay of AD patient derived induced pluripotent stem cells by a novel mechanism that does not target theorsecretaseOur overall goal in this PhaseSBIR application is to further study the best three candidates AAthat were selected for their efficacy in reducing Aandand their analogsfor their pharmacokinetic and drug like propertiesso that we may arrive at one or two candidates that may be tested for their efficacy in vivo and be taken though preclinical development as novel oral disease modifying drugs for AD