A method for inhibiting the activity of serine proteinase in biological systems includes administering to the system a serine proteinase inhibitory amount of a hydrophobic 4-de(dimethylamino) tetracycline. The method reduces tissue destruction during inflammation resulting from the activity of human leukocyte elastase. The method is used for pharmaceutical and cosmetic purposes.

Serine proteinase inhibitory activity by hydrophobic tetracycline

Publisher Summary This chapter discusses the inhibition strategies published over the past two years and the current status of proteinases released by neutrophils and mononuclear phagocytes. Neutrophils, when activated, release a complex assortment of agents that can destroy normal cells and dissolve connective tissues. Lysosomal cysteine proteinases, with pH optima in the acid range and three neutral swine proteinases, elastase, cathepsin G, and protinase-3, are stored in the azurophil granules. Two metalloproteinases, collagenase, and gelatinase are found in specific secondary and tertiary granules, respectively. In contrast to neutrophils, macrophages are long-lived cells, with important synthetic capabilities and major secretory activities, and with a remarkable potential for functional differentiation. Macrophages lack sub-cellular storage organelles comparable to neutrophil granules and do not contain serine proteinases. Proteinases must perform their normal functions during homeostasis, as well as disease-related tissue destruction, in settings ostensibly dominated by high concentrations of powerful endogenous inhibitors (anti-proteinases) that can rapidly and irreversibly inhibit proteinase activity in plasma and interstitial fluids. Triggered neutrophils have the ability to create a subjacent sequestered environment from which endogenous inhibitors are excluded and released proteinases can act unmolested. Interleukin-1β (IL-1β) is a major mediator of inflammation and potent bone resorptive cytokine that also mediates soft tissue destruction through the stimulation of prostaglandin production and the induction of collagenase and other proteinases. At least nine distinct members of the matrixin family, produced by connective tissue cells, have been identified and broadly subdivided into three categories on the basis of substrate specificity: the collagenases, gelatinases, and stromelysins. Matrix metalloproteinases (MMPs) are all Zn 2+ and Ca 2+ requiring enzymes that are secreted in inactive proforms, activated by loss of a propeptide of molecular weight -10,000, and then subject to inhibition by tissue inhibitor of metalloproteinase (TIMP)-1 or -2. These enzymes have the combined ability to degrade all the components of the extracellular matrix. Despite the many potent in vitro inhibitors, very few orally bioavailable proteinase inhibitors have been reported and evaluated in a clinical setting targeted for inflammatory diseases.

Chapter 20. Proteinases in Inflammation

We report the synthesis of a series of diphenylmethane-based oligomers containing anionic and lipophilic functionalities that are potent inhibitors of human leukocyte elastase (HLE). The enzyme inhibition is regulated by the size of the oligomer, as well as, the number of charges. Lipophilicity is an important element in determining potency and specificity against other basic enzymes. Compounds whose scaffolds contain three phenoxyacetic acid groups and three alkyl ethers are competitive and specific inhibitors of HLE with Ki = 20 nM. The mechanism of action of this class of compounds is believed to involve multidendate interactions with the surface of HLE near the active site which prevents substrate access to the catalytic site.

Anionic- and Lipophilic-Mediated Surface Binding Inhibitors of Human Leukocyte Elastase

Slow-onset interactions between modifiers and their target enzymes are common in living cells and physiological fluids. This chapter aims at supporting the analysis of such interactions in the test tube by discussing the properties of various mechanisms and providing diagnostic methods to discriminate between them. That this is not a mere academic exercise is demonstrated by the importance of several slow-onset enzyme inhibitors that have been approved as drugs. Knowing their properties in vitro is the logical starting point for interpreting their mode of action at target sites in cells and body fluids.

Slow-Onset Enzyme Inhibition

Synthesis and evaluation of CE-0266: A new human neutrophil elastase inhibitor

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Synthesis and evaluation of CE-0266: A new human neutrophil elastase inhibitor