Optimization of small molecule SERCA2b activators to inhibit neuron loss in Alzheimer's disease

Alzheimer s diseaseADis an immense national public health burdenIt is theth leading cause of death in
the US with overmillion Americans sufferingand costs of over $billion in health care and related
expensesThis patient population is expected to almost triple over the nextyearsDespite this urgent needthere are currently no disease modifying agents approvedNeuron loss is the only physiological phenomena
that has been directly linked to the cognition loss in patientsand a major cause of this brain cell death is
endoplasmic reticulumERstress induced apoptosis caused by disrupted intracellular CahomeostasisBy
targeting correction of this altered CastateNeurodon has developed a series of novel small molecule
positive allosteric modulatorsPAMsof the major ER Cahandling proteinsarco endoplasmic reticulum
CaATPaseSERCAOur PAMs rescue brain cells in vitro and in vivoand improve memory and cognition in
the APP PSdouble transgenic mouse model of ADThese results support SERCA activation as a target for
the development of disease modifying therapeutics for ADThe overall goal of Neurodon is the development of
effective and orally available drugs to slow or halt AD progressionIn this initial Phaseproposal we will
partner with the chemistry expertise and facilities at Northwestern University to deliver advanced leads having
potential for oral availability and improved efficacyThese goals will be accomplished by pursuing the following
AimsPerform hit to lead and lead optimization on our novel series of SERCA b PAMs to improve biological
activity and physical propertiesUsing synthetic chemistrystructure based drug designand ADME profilingwe will optimize our novel series to improve efficacy and enable oral administrationTo characterize our
synthesized SERCA PAMs in cellular and functional assays to assess their efficacy and prioritize development
candidatesWe have developedcomplimentary assays to rapidly vet our newly synthesized leads for
potential as drug development candidatesUltimatelythe results of these proposed Aims will be the delivery of
drug molecules to be advanced to candidate seeking development activities including efficacy and toxicological
studies in PhaseThis proposal aims to optimize a series of novelbrain penetrant small molecules that have been
shown to inhibit endoplasmic reticulumERstress induced cell death in a model of Alzheimer s
diseaseADER stress induced apoptosis has been identified as a major cause of the brain cell loss
in AD patient brainsand our class of small molecules targets a novel cause of ER stressdysfunctional SERCArescuing cells in cell based and animal modelsand improving memory and
cognition in a transgenic mouse model of ADThis proposal will optimize our series to provide
development candidates and is thus directly relevant to NIH s mission of reducing the burden of
illness by seeking to develop systemically active molecules to slow or halt neurodegeneration in AD