2. Academic Validation
  3. Discovery and structure activity relationships of 7-benzyl triazolopyridines as stable, selective, and reversible inhibitors of myeloperoxidase

Discovery and structure activity relationships of 7-benzyl triazolopyridines as stable, selective, and reversible inhibitors of myeloperoxidase

  • Bioorg Med Chem. 2020 Nov 15;28(22):115723. doi: 10.1016/j.bmc.2020.115723.
Scott A Shaw 1,  Benjamin P Vokits 2,  Andrew K Dilger 2,  Andrew Viet 2,  Charles G Clark 2,  Lynn M Abell 2,  Gregory A Locke 2,  Gerald Duke 2,  Lisa M Kopcho 2,  Ashok Dongre 2,  Ji Gao 2,  Arathi Krishnakumar 2,  Sutjano Jusuf 2,  Javed Khan 2,  Steven A Spronk 2,  Michael D Basso 2,  Lei Zhao 2,  Glenn H Cantor 2,  Joelle M Onorato 2,  Ruth R Wexler 2,  Franck Duclos 2,  Ellen K Kick 2
Affiliations

Affiliations

  • 1 Bristol Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543-5400, United States. Electronic address: [email protected].
  • 2 Bristol Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543-5400, United States.
PMID: 33007547 DOI: 10.1016/j.bmc.2020.115723
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.

Keywords

Atherosclerosis; Myeloperoxidase; Triazolopyridine.

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