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Potent Triazolopyridine Myeloperoxidase Inhibitors.

ABSTRACT: Myeloperoxidase (MPO) generates reactive oxygen species that potentially contribute to many chronic inflammatory diseases. A recently reported triazolopyrimidine MPO inhibitor was optimized to improve acid stability and remove methyl guanine methyl transferase (MGMT) activity. Multiple synthetic routes were explored that allowed rapid optimization of a key benzyl ether side chain. Crystal structures of inhibitors bound to the MPO active site demonstrated alternate binding modes and guided rational design of MPO inhibitors. Thioether 36 showed significant inhibition of MPO activity in an acute mouse inflammation model after oral dosing.

SUBMITTER: Wurtz NR

PROVIDER: S-EPMC6295853 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Potent Triazolopyridine Myeloperoxidase Inhibitors.

Wurtz Nicholas R NR Viet Andrew A Shaw Scott A SA Dilger Andrew A Valente Meriah N MN Khan Javed A JA Jusuf Sutjano S Narayanan Rangaraj R Fernando Gayani G Lo Fred F Liu Xiaoqin X Locke Gregory A GA Kopcho Lisa L Abell Lynn M LM Sleph Paul P Basso Michael M Zhao Lei L Wexler Ruth R RR Duclos Franck F Kick Ellen K EK

ACS medicinal chemistry letters 20181101 12

Myeloperoxidase (MPO) generates reactive oxygen species that potentially contribute to many chronic inflammatory diseases. A recently reported triazolopyrimidine MPO inhibitor was optimized to improve acid stability and remove methyl guanine methyl transferase (MGMT) activity. Multiple synthetic routes were explored that allowed rapid optimization of a key benzyl ether side chain. Crystal structures of inhibitors bound to the MPO active site demonstrated alternate binding modes and guided ration ...[more]

PMID: 30613322

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2018-12-10 | GSE118589 | GEO

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