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Cathepsin enzyme inhibitors

Figure 11.8 Different structure-selectivity relationships. Structurally similar as well as diverse molecules display different selectivity patterns in a set of cathepsin enzyme inhibitors. SR means selectivity ratio and is calculated as the quotient of the... Figure 11.8 Different structure-selectivity relationships. Structurally similar as well as diverse molecules display different selectivity patterns in a set of cathepsin enzyme inhibitors. SR means selectivity ratio and is calculated as the quotient of the...
Enzyme inhibitors (e.g. metalloproteinases, cathepsin K) Purinergic modulators... [Pg.280]

When the target enzyme is difficult to obtain, related enzymes could be used to provide insights in the design of novel ligands. For example, papain was used to design a class of potent cathepsin K inhibitors [33] spanning both sides of the papain active site. However, fine-tuning these inhibitors to produce more potent ones required the use of the crystal structure of cathepsin K itself [34],... [Pg.28]

More detailed studies of epimerization in the azepanone series indicated that these compounds were configurationally stable over a pharmaceutically relevant time-scale [19]. Structure-activity relationships developed in previous series were applied successfully to the azepanone scaffold, yielding extremely potent enzyme inhibitors that exhibited good diastereomeric selectivity as well as reasonable selectivity versus cathepsin K homologues. [Pg.138]

The simplest member of this family of inhibitors, the methoxy-methyl ketone (Fig. 5.8a), has been studied as a complex with papain [14]. This enzyme-inhibitor complex shows binding of the peptide portion of the inhibitor on the prime side of the active site in a manner similar to that seen for Cbz-Leu-Leu-Leu-aldehyde (Fig. 5.2d) bound to papain. In contrast to the thiohemi-acetal seen with the aldehyde, the carbonyl of the methoxy-methyl ketone (Fig. 5.8a) is quite distant from the active site thiol, with no possibility of covalent interaction. Therefore, this inhibitor meets the criteria for class I inhibition. The n-propyloxy ketone (Fig. 5.8b), which also binds on the prime side of the active site, has the ketone in close proximity to the active site thiol of cathepsin K, as seen in the structure of the inhibitor-enzyme complex [20]. Covalent attachment appears to have followed from... [Pg.140]

For selectivity searching, three enzymes, cathepsins K, L, and S, were targeted and cathepsin K inhibitors selective for K over L and S were used as reference molecules in order to identify new cathepsin K-selective inhibitors [43]. [Pg.311]

After testing the compounds for enzyme inhibition in spectrophotometric assays for cathepsin S and L and in a fluorometric assay for cathepsin K, three new cathepsin K inhibitors could be identified, as shown in Figure 11.10. [Pg.313]

Inhibition of cathepsin H by the inhibitor is rapid, reaching maximal levels within 15 seconds after addition of the inhibitor at 0°C. Kinetical studies indicate that the purified inhibitor inhibited papain noncom-petitively and pseudoirreversibly. The inhibitor inhibits cathepsin H by forming an enzyme- inhibitor complex in a molar ratio of 1 1. When cathepsin H is preincubated with E-64, formation of the enzyme-inhibitor complex is retarded. Conversely, when H-labeled E-64 is added to the reaction mixture after the enzyme-inhibitor complex is formed, incorporation of H-labeled E-64 into cathepsin H is slight. Those results suggest that the thiol proteinase inhibitor binds to the active site region of thiol proteinases. [Pg.91]

Cathepsin G is an enzyme with dual chymotrypsin and trypsin-like specificity and as a leukocyte proteinase it is involved in the early stages of the immune response. Synthesis and inhibitory activity of a-aminoalkylpho-sphonates diphenyl esters as irreversible cathepsin G inhibitors has been described by Lesner et al. The phosphonates (244) and (245) turned out to be especially active. " ... [Pg.280]


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See also in sourсe #XX -- [ Pg.724 ]




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Enzyme cathepsins

Enzyme inhibitors

Enzymes enzyme inhibitor

Inhibitors, cathepsin

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