Structural variants of Abeta oligomer displacing small molecules

Abstract Project Summary Cognition Therapeutics Inc s mission is to develop effective therapeutics for Alzheimer s disease AD Recent scientific discoveries have identified oligomers of the brain protein Amyloid beta A Os as toxic culprits in disease progression Cognition has identified a subset of sigma receptor binding modulators that displace A Os from neurons and block the downstream pathological signaling that inhibits memory formation This approach is in contrast to traditional A O intervention strategies which either block the expression of Abeta or clear A Os or block their formation These compounds should prevent further A O 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 Alzheimer s patients Pharmaceutical industry efforts targeted specifically at A O displacement are currently limited Cognition Therapeutics is one of the only companies uniquely focused on discovery of small molecule A O displacing therapeutics Cognition Therapeutics has discovered two CNS drug like series of A O displacing compounds Analogs of both series displace oligomers from neurons and completely block A O induced membrane trafficking changes and synapse loss Members of these series are highly brain penetrant and completely block oligomer induced memory deficits in Alzheimer s disease mouse models Drug candidate CT from Series is progressing through clinical trials Cognition now seeks to leverage the accumulated knowledge of SAR from both series plus the known sigma receptor binding modulators to define and develop new lead candidates for the clinical pipeline Additional candidates with different physicochemical and structural properties would de risk the clinical development to NDA process for these first in class treatments This proposal will allow us to expand our portfolio of A O displacing molecules with the goal of identifying orally efficacious candidates for further development as therapeutics for AD Project Narrative Cognition Therapeutics Inc s mission is to develop effective therapeutics for Alzheimer s disease which target the toxic Abeta oligomer A O protein In contrast to other A O intervention strategies which either block the expression of Abeta or clear A Os or block their formation Cognition Therapeutics CogRx has chosen a novel oligomer displacement approach to targeting A Os using compounds to displace oligomers from their binding site on neuronal synapses This approach protects neurons from toxic oligomer assault and allows them to regenerate lost synapses We have discovered and developed two orally available CNS drug like lead series of sigma receptor modulators that displace the A O protein from neuronal cells in the brain Analogs from both series prevent memory deficits in Alzheimer s disease mouse models This proposal requests funding in order to discover and develop new leads for the clinical pipeline leveraging our accumulated knowledge of the structure activity relationships of both series as well as known sigma receptor modulators Successful advancement of a A O displacing drug would significantly impact the lives of the million patients worldwide suffering from AD and MCI for whom no disease modifying treatment exists