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

Shaw SA, Vokits BP, Dilger AK, Viet A, Clark CG, Abell LM, Locke GA, Duke G, Kopcho LM, Dongre A, Gao J, Krishnakumar A, Jusuf S, Khan J, Spronk SA, Basso MD, Zhao L, Cantor GH, Onorato JM, Wexler RR, Duclos F, Kick EK
Bioorg Med Chem 28 115723 (2020)
Related entries: 6wxz, 6wy0, 6wy5, 6wyd

Cited: 5 times
EuropePMC logo PMID: 33007547

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.

Articles citing this publication (5)

  1. Computational Screening for the Anticancer Potential of Seed-Derived Antioxidant Peptides: A Cheminformatic Approach. Chai TT, Koh JA, Wong CC, Sabri MZ, Wong FC. Molecules 26 7396 (2021)
  2. Purification, Identification and Characterization of Antioxidant Peptides from Corn Silk Tryptic Hydrolysate: An Integrated In Vitro-In Silico Approach. Ong JH, Koh JA, Cao H, Tan SA, Abd Manan F, Wong FC, Chai TT. Antioxidants (Basel) 10 1822 (2021)
  3. 2-Oxabicyclo[2.2.2]octane as a new bioisostere of the phenyl ring. Levterov VV, Panasiuk Y, Sahun K, Stashkevych O, Badlo V, Shablykin O, Sadkova I, Bortnichuk L, Klymenko-Ulianov O, Holota Y, Lachmann L, Borysko P, Horbatok K, Bodenchuk I, Bas Y, Dudenko D, Mykhailiuk PK. Nat Commun 14 5608 (2023)
  4. Curcumin and n-acetylcysteine cocrystal produced with supercritical solvent: characterization, solubility, and preclinical evaluation of antinociceptive and anti-inflammatory activities. Paulazzi AR, Alves BO, Zilli GAL, Dos Santos AE, Petry F, Soares KD, Danielli LJ, Pedroso J, Apel MA, Aguiar GPS, Siebel AM, Oliveira JV, Müller LG. Inflammopharmacology 30 327-341 (2022)
  5. Inhibition of Myeloperoxidase. Soubhye J, Furtmüller PG, Dufrasne F, Obinger C. Handb Exp Pharmacol 264 261-285 (2021)


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