Discovery of Investigational Drug CT1812, an Antagonist of the Sigma-2 Receptor Complex for Alzheimer’s Disease
Gilbert M. Rishton, Gary C. Look, Zhi‐Jie Ni, Jason Zhang, Yingcai Wang, Yaodong Huang, Xiaodong Wu, Nicholas J. Izzo, Kelsie M. LaBarbera, Colleen S. Limegrover, Courtney Rehak, Raymond Yurko, Susan M. Catalano
Abstract
An unbiased phenotypic neuronal assay was developed to measure the synaptotoxic effects of soluble Aβ oligomers. A collection of CNS druglike small molecules prepared by conditioned extraction was screened. Compounds that prevented and reversed synaptotoxic effects of Aβ oligomers in neurons were discovered to bind to the sigma-2 receptor complex. Select development compounds displaced receptor-bound Aβ oligomers, rescued synapses, and restored cognitive function in transgenic hAPP Swe/Ldn mice. Our first-in-class orally administered small molecule investigational drug 7 (CT1812) has been advanced to Phase II clinical studies for Alzheimer’s disease.