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Open Access Publications from the University of California

Inhibition of myeloperoxidase: evaluation of 2H-indazoles and 1H-indazolones.

  • Author(s): Roth, Aaron
  • Ott, Sean
  • Farber, Kelli M
  • Palazzo, Teresa A
  • Conrad, Wayne E
  • Haddadin, Makhluf J
  • Tantillo, Dean J
  • Cross, Carroll E
  • Eiserich, Jason P
  • Kurth, Mark J
  • et al.

Myeloperoxidase (MPO) produces hypohalous acids as a key component of the innate immune response; however, release of these acids extracellularly results in inflammatory cell and tissue damage. The two-step, one-pot Davis-Beirut reaction was used to synthesize a library of 2H-indazoles and 1H-indazolones as putative inhibitors of MPO. A structure-activity relationship study was undertaken wherein compounds were evaluated utilizing taurine-chloramine and MPO-mediated H2O2 consumption assays. Docking studies as well as toxicophore and Lipinski analyses were performed. Fourteen compounds were found to be potent inhibitors with IC50 values <1μM, suggesting these compounds could be considered as potential modulators of pro-oxidative tissue injury pertubated by the inflammatory MPO/H2O2/HOCl/HOBr system.

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