Naphthalenes as inhibitors of myeloperoxidase: direct and indirect mechanisms of inhibition.
Control of myeloperoxidase (MPO) may be an important consideration in disorders where excessive PMN elastase activity is a significant factor. There are, however, two mechanisms for the apparent regulation of MPO: 1) inhibit the enzyme directly, and ii) prevent the ensuing HOC1 induced oxidation by using a surrogate reducing agent. Appropriate methodology has been devised to distinguish true MPO inhibitors. With the exception of NaN3, many MPO inhibitors fall into the latter category and do not actually regulate the enzyme. Several potent organic inhibitors have been discovered, which, because of their structural selectivity, appear to associate specifically with a binding site on the enzyme, rather than attaching indiscriminately to a hydrophobic domain. By controlling the enzyme, these compounds protect alpha-1-PI from MPO induced damage, and could serve better than antioxidants to define the role of MPO in elastase induced injury.
Egan
R W
RW
Merck Sharp and Dohme Research Laboratories, Rahway, New Jersey 07065.
Hagmann
W K
WK
Gale
P H
PH
D000818:Animals; D001665:Binding Sites; D003962:Dianisidine / Q000378:metabolism; D004285:Dogs; D006861:Hydrogen Peroxide / Q000378:metabolism; D006997:Hypochlorous Acid; D019272:Leukocyte Elastase; D008715:Methionine / Q000494:pharmacology; D015394:Molecular Structure; D009281:Naphthalenes / Q000494:pharmacology*; D010084:Oxidation-Reduction; D010196:Pancreatic Elastase / Q000378:metabolism; D009195:Peroxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D000515:alpha 1-Antitrypsin / Q000378:metabolism
D009281:Naphthalenes; D000515:alpha 1-Antitrypsin; D006997:Hypochlorous Acid; D008715:Methionine; D006861:Hydrogen Peroxide; D009195:Peroxidase; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase; D003962:Dianisidine