Design, synthesis and identification of N, N-dibenzylcinnamamide (DBC) derivatives as novel ligands for α-synuclein fibrils by SPR evaluation system

• Published in: Bioorganic & medicinal chemistry 2020-04, Vol.28 (7), p.115358-115358, Article 115358
• Main Authors: Chen, Yan-Fei, Bian, Jiang, Zhang, Peng, Bu, Lu-Lu, Shen, Yan, Yu, Wen-Bo, Lu, Xiu-Hong, Lin, Xin, Ye, De-Yong, Wang, Jian, Chu, Yong
• Format: Article
• Language: English
• Subjects: alpha-Synuclein - chemistry; Brain; Cinnamates - chemistry; Cinnamates - pharmacology; Drug Design; F-labeled stable isotope tracer; Humans; Ligands; Molecular Structure; N, N-dibenzylcinnamamide; Parkinson's disease; PET tracer; Positron-Emission Tomography; Radioligand Assay; SPR; α-synuclein
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2020.115358

[Display omitted] •We have synthesized a series of novel N, N-dibenzylcinnamamide (DBC) compounds with a high affinity for α-syn aggregates.•We initially established an efficient biological system based on SPR technology suitable for large-scale evaluation of small molecules.•The F-labeled DBC compound 5–41 was approved to be a new lead compound for developing PET radiotracer for PD diagnosis. PET imaging of α-synuclein (α-syn) deposition in the brain will be an effective tool for earlier diagnosis of Parkinson's disease (PD) due to α-syn aggregation is the widely accepted biomarker for PD. However, the necessary PET radiotracer for imaging is clinically unavailable until now. The lead compound discovery is the first key step for the study. Herein, we initially established an efficient biologically evaluation system well in highthroughput based on SPR technology, and identified a novel class of N, N-dibenzylcinnamamide (DBC) compounds as α-syn ligands through the assay. These compounds were proved to have high affinities against α-syn aggregates (KD