Optimization of sigma-2 receptor modulators for the treatment of cognitive dysfunction

AbstractProject Summary Cognition Therapeutics IncsCogrxmission is to develop effective therapeutics for Alzheimer s diseaseADOligomers of the brain protein Amyloid betaA Oshave been identified as toxic components that are involved with disease progressionCognition has identified a subset of sigmareceptor binding modulators that displaces A Os from synaptic receptor sites and clears them into the cerebral spinal fluidCSFThese compounds accomplish this by allosterically modulating a key protein regulator of oligomer receptorsthe sigmaPGRMCprotein complexthus destabilizing the oligomer binding site and increasing the off rate of oligomerswhich are then rapidly cleared into the CSFwithin hoursAs a resultCTrestores synapse number and cognitive performance to normal in preclinical AD mouse modelsIzzo et alabCogRx has discovered two CNS drug like lead series of A O displacing compoundsAnalogs from these series displace oligomers from neurons and completely block A O induced membrane trafficking changes and synapse loss in vitroMembers of these series are highly brain penetrant and completely block oligomerinduced memory deficits in Alzheimer s disease mouse modelsDrug candidate CTfrom Seriesis progressing through Phase I clinical trials with an open IND in the USWe have now turned our attention to identifying new candidates to provide a measure of risk mitigation in the event that our current candidate falters due to unforeseen issuesCognition and Temple University identified a new lead series of sigmareceptor binding modulatorsoriginally discovered at Temple Universitythat block A O induced membrane trafficking changesThe feasibility of medicinal chemistry optimization was established in a Phase I STTR projectThis Phase II proposal seeks to further optimize this new series by synthesis and testing of new analogs designed to improve pharmacological and ADME propertiesThis proposal will allow us to expand our portfolio of sigmareceptor binding modulators with the goal of identifying orally efficacious candidates for further development as therapeutics for AD Cognition Therapeutics is a pioneer in the development of high affinity sigmareceptor binding modulators that displace A Os from neuronal receptors that mediate synaptotoxicityclear them into the cerebral spinal fluidcompletely eliminate synapse loss and restore normal memory function in transgenic animalsIn collaboration with Temple UniversityCognition has identified a new series of sigmareceptor modulatorsinitially discovered by Temple researcherswhich displace A OsThe requested funding will enable the optimization of this series of small molecules in order to identify suitable bioavailablepotent and selective INDcandidatesThese studies will lead to future work to advanced candidates through IND enabling studies and eventual clinical trialsAn optimized A O displacing sigmareceptor modulator IND candidate would further expand the portfolio of small molecule drugs available to reverse AD and MCI symptoms and block disease progression