New piperazines effecting Abeta oligomer displacement from neuronal receptors

DESCRIPTION provided by applicant Cognition Therapeutics Inc andapos s mission is to develop effective therapeutics for Alzheimerandapos s disease Recent scientific discoveries have identified oligomers of the brain protein Abeta as toxic culprits in the disease process Cognition has discovered therapeutic molecules that displace Abeta oligomers from neurons and block the downstream pathological signaling that inhibits memory formation These therapeutic small molecules should prevent further oligomer induced damage and unmask existing memory capacity as synapses recover These molecules act through modulating a newly identified receptor target They are hypothesized to be disease modifying treatments that would be effective throughout the course of the disease and significantly impact the lives of millions of Alzheimerandapos s patients Pharmaceutical industry efforts targeted specifically at Abeta oligomer blockade are currently limited Cognition Therapeutics is one of the only companies uniquely focused on discovery of small molecule oligomer displacing therapeutics We have discovered a CNS drug like lead series of oligomer displacing compounds the CT Series Analogs in this series displace oligomers from neurons and completely block Abeta oligomer induced membrane trafficking changes and synapse loss Members of this series are highly brain penetrant and completely block oligomer induced memory deficits in Alzheimerandapos s disease mouse models Further preclinical development of these analogs is progressing However new structural variants with different physicochemical profiles will provide a measure of risk mitigation in the event that our current candidates fail to advance through the clinic due to unforeseen issues We propose to explore a new piperazine variant of the CT series This new variant would possess physiochemical properties previously unexplored in the current series This proposal will allow us to expand our portfolio of Abeta oligomer displacing compounds and establish the feasibility of these variants to be optimized with the goal of obtaining orally efficacious candidates for further development as therapeutics for AD

PUBLIC HEALTH RELEVANCE Abeta oligomers trigger synaptic dysfunction and lead to the cognitive decline in MCI and early AD Prolonged oligomer exposure leads to more severe synaptotoxicity memory deficits and accumulated pathology Therapeutics which displaces oligomers from neuronal binding sites should block and potentially reverse disease symptoms and progress Cognition Therapeutics has discovered first in class high affinity oligomer displacing molecules that mediate synaptotoxicity completely eliminate synapse loss and restore memory to normal in transgenic animals The requested funding will enable the preparation and in depth testing of new variant of these molecules with different physicochemical properties from our parent series These early feasibility studies will facilitate future work for optimization and development of advanced compounds to preclinical studies and eventual clinical trials Such an optimized Abeta oligomer displacing IND candidate would be expand our portfolio of novel small molecule drugs to reverse AD and MCI symptoms and block disease progression