4-Acyl-3,4-dihydropyrrolo[1,2- a]pyrazine Derivative Rescued the Hippocampal-Dependent Cognitive Decline of 5XFAD Transgenic Mice by Dissociating Soluble and Insoluble Aβ Aggregates

Abstract

Cerebral amyloid-β (Aβ) deposition is a representative hallmark of Alzheimer's disease (AD). Development of Aβ-clearing small molecules could be an advantageous therapeutic strategy for Aβ clearance considering the advantages in terms of side effects, cost-effectiveness, stability, and oral bioavailability. Here, we report an Aβ-dissociating small molecule, YIAD-0121, a derivative of 4-acyl-3,4-dihydropyrrolo[1,2-a]pyrazine. Through a series of anti-Aβ screening assays, YIAD-0121 was identified to inhibit Aβ aggregation and dissociate preformed Aβ fibrils in vitro. Furthermore, the administration of YIAD-0121 in 5XFAD transgenic AD mice inhibited the increase of cerebral Aβ aggregation and progression of hippocampus-dependent cognitive decline, with ameliorated neuroinflammation.

Keywords: 4-acyl-3,4-dihydropyrrolo[1,2-a]pyrazines; Alzheimer’s disease; Aβ clearance; Aβ-dissociating small molecules.