Discovery of Potent and Selective Inhibitors for ADAMTS-4 through DNA-Encoded Library Technology (ELT).
Basic Information
ID: ALA3621096
Journal: ACS Med Chem Lett
Title: Discovery of Potent and Selective Inhibitors for ADAMTS-4 through DNA-Encoded Library Technology (ELT).
Authors: Ding Y, O'Keefe H, DeLorey JL, Israel DI, Messer JA, Chiu CH, Skinner SR, Matico RE, Murray-Thompson MF, Li F, Clark MA, Cuozzo JW, Arico-Muendel C, Morgan BA.
Abstract: The aggrecan degrading metalloprotease ADAMTS-4 has been identified as a novel therapeutic target for osteoarthritis. Here, we use DNA-encoded Library Technology (ELT) to identify novel ADAMTS-4 inhibitors from a DNA-encoded triazine library by affinity selection. Structure-activity relationship studies based on the selection information led to the identification of potent and highly selective inhibitors. For example, 4-(((4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-6-(((4-methylpiperazin-1-yl)methyl)amino)-1,3,5-triazin-2-yl)amino)methyl)-N-ethyl-N-(m-tolyl)benzamide has IC50 of 10 nM against ADAMTS-4, with >1000-fold selectivity over ADAMT-5, MMP-13, TACE, and ADAMTS-13. These inhibitors have no obvious zinc ligand functionality.
CiteXplore: 26288689
DOI: 10.1021/acsmedchemlett.5b00138
Patent ID: ┄