Abstract
Discovery of oxazolidinone-based heterocycles as subtype selective sigma-2 ligands
Highlights
Extensive research efforts have linked Alzheimer’s disease progression to the formation of β-amyloid plaques and neurofibrillary tangles in the cortical and subcortical regions of the brain, a theory known as the Amyloid Hypothesis
-amyloid plaques, a hallmark feature of Alzheimer’s disease.[3]. Clinical trials targeting this pathway via small molecule such as verubecestat (1)[4] and semagacestat (2)[5], as well as monoclonal antibodies such as Bapineuzumab and Solanezuma, have ended in failure.[6]
Their efforts lead to the identification of CT1812, a potent σ2 ligand (Ki = 8.5 nM), that is efficacious in the hAPP Swe/Ldn mouse model and is currently undergoing clinical trials as a potential Alzheimer’s disease therapy.[17]
Summary
Extensive research efforts have linked Alzheimer’s disease progression to the formation of β-amyloid plaques and neurofibrillary tangles in the cortical and subcortical regions of the brain, a theory known as the Amyloid Hypothesis. Preliminary assessment of initial compounds prepared in this series by the Psychoactive Drug Screening Program (PDSP) demonstrated that members of this family that are potent σ2 binders with varying levels of σ1/σ2 selectivity. Given the therapeutic potential of this receptor, a drug discovery program focused on the identification of novel, druglike functionalized 5-(piperazin-1-ylmethyl)oxazolidin-2-ones with potent σ2 binding was established. (3-benzyl-2-oxooxazolidin-5-yl)methyl 4-methylbenzenesulfonate was prepared according to the procedure of (3-(cyclohexylmethyl)-2-oxooxazolidin-5-yl)methyl 4-methylbenzenesulfonate except cyclohexyl methylamine was replaced with benzyl amine.
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