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

DESCRIPTION provided by applicant Cognition Therapeutics Inc andapos s mission is to develop effective therapeutics for Alzheimerandapos s disease AD Recent scientific discoveries have identified oligomers of the brain protein A as toxic culprits in disease progression Cognition in partnership with Temple University has identified a novel series of sigma receptor binding modulators that displace oligomers from neurons and block the downstream pathological signaling that inhibits memory formation These therapeutics should prevent further A oligomer induced damage and unmask existing memory capacity as synapses recover These receptor binding modulators are hypothesized to be disease modifying treatments that would be effective throughout the course of the disease and significantly impact the lives of the millions of Alzheimerandapos s patients Pharmaceutical industry efforts targeted specifically at A oligomer displacement are currently limited Cognition Therapeutics is one of the only companies uniquely focused on discovery of small molecule A oligomer displacing therapeutics We have discovered two CNS drug like lead series of A oligomer displacing compounds Analogs in these series displace oligomers from neurons and completely block A oligomer induced membrane trafficking changes and synapse loss Members of these series are highly brain penetrant and completely block oligomer induced memory deficits in Alzheimerandapos s disease mouse models Development of a clinical candidate is progressing We 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 issues We propose to optimize Temple Universityandapos s series of novel sigma receptor binding modulators by synthesis and testing of new analogs designed to improve pharmacological and ADME properties This proposal will allow us to expand our portfolio of sigma receptor binding modulators with the goal of identifying orally efficacious candidates for further development as therapeutics for AD

PUBLIC HEALTH RELEVANCE Amyloid beta oligomers AOs trigger synaptic dysfunction and lead to the cognitive decline in mild cognitive impairment MCI and early Alzheimerandapos s disease AD Prolonged oligomer exposure leads to more severe synaptotoxicity memory deficits and associated pathologies Novel therapeutics which displaces AOs from neurons should block and potentially reverse disease symptoms and progression Cognition Therapeutics is a pioneer in the development of high affinity sigma receptor binding modulators that displace AOs from neuronal receptors that mediate synaptotoxicity completely eliminate synapse loss and restore normal memory function in transgenic animals In collaboration with Temple University Cognition has identified a new series of sigma receptor modulators initially discovered by Temple researchers which exhibit potential to displace AOs The requested funding will enable the preparation and testing of new potent analogs of these small molecules with improved properties for oral administration These early feasibility studies will facilitate future work to optimize and develop advanced compounds for preclinical studies and eventual clinical trials An optimized sigma receptor modulator IND candidate that displaces AOs would further expand the portfolio of small molecule drugs available to reverse AD and MCI symptoms and block disease progression