Discovery and structure activity relationships of 7-benzyl triazolopyridines as stable, selective, and reversible inhibitors of myeloperoxidase. Issue 22 (15th November 2020)

• Record Type: Journal Article
• Authors: Shaw, Scott A.; Vokits, Benjamin P.; Dilger, Andrew K.; Viet, Andrew; Clark, Charles G.; Abell, Lynn M.; Locke, Gregory A.; Duke, Gerald; Kopcho, Lisa M.; Dongre, Ashok; Gao, Ji; Krishnakumar, Arathi; Jusuf, Sutjano; Khan, Javed; Spronk, Steven A.; Basso, Michael D.; Zhao, Lei; Cantor, Glenn H.; Onorato, Joelle M.; Wexler, Ruth R.; Duclos, Franck; Kick, Ellen K.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 28:Issue 22(2020)
• Publication Date: 2020-11-15
• Subjects: Myeloperoxidase -- Atherosclerosis -- Triazolopyridine; ADP adenosine diphosphate -- APF aminophenyl fluorescein -- AR amplex red -- AUCtot total exposure -- Cl-Tyr chlorotyrosine -- Cmax maximum plasma concentration -- CYP cytochrome P450 -- dba dibenzylideneacetone -- DCM dichloromethane -- HDL high density lipoprotein -- I.V. intravenous -- LDL low density lipoprotein -- MGMT methyl guanine methyl transferase -- MPO myeloperoxidase -- PAMPA parallel artificial membrane permeability assay -- ROS reactive oxygen species -- TEA triethylamine -- TES triethylsilyl -- TFA trifluoroacetic acid -- THF tetrahydrofuran -- TPO thyroid peroxidase -- TrCl trityl chloride; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2020.115723
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Myeloperoxidase (MPO) is a heme peroxidase found in neutrophils, monocytes and macrophages that efficiently catalyzes the oxidation of endogenous chloride into hypochlorous acid for antimicrobial activity. Chronic MPO activation can lead to indiscriminate protein modification causing tissue damage, and has been associated with chronic inflammatory diseases, atherosclerosis, and acute cardiovascular events. Triazolopyrimidine 5 is a reversible MPO inhibitor; however it suffers from poor stability in acid, and is an irreversible inhibitor of the DNA repair protein methyl guanine methyl transferase (MGMT). Structure-based drug design was employed to discover benzyl triazolopyridines with improved MPO potency, as well as acid stability, no reactivity with MGMT, and selectivity against thyroid peroxidase (TPO). Structure-activity relationships, a crystal structure of the MPO-inhibitor complex, and acute in vivo pharmacodynamic data are described herein.