Human elastase

Dll. Del Mar, E. G., Brodrick, J. W., Geokas, M. C., and Largman, C., Effect of oxidation of methionine in a peptide substrate for human elastases A model for inactivation of alpha 1-protease inhibitor. Biochem. Biophys. Res. Commun. 88,346-350 (1979). 

Keywords human elastase, protease inhibitors, silicon diol, privileged structure. 

Molecular modeling studies were performed using the crystal structure of human elastase (pdb code IHNE), Sybyl molecular modeling software and a Tripos forcefield. An assumption was made that the silicon diol forms a covalent bond with the catalytic serine residue, Serl95. 

Human elastase-1 (EC 3.4.21.36 no systematic name El) is an anionic protease belonging to the family of serine proteases. It is a carboxyendopeptidase that catalyzes hydrolysis of native elastin, the major structural fibrous protein in connective tissue, with a special affinity for the carboxyl group of alanine, valine, and leucine. 

Human elastase Good orai bioavaiiabiiity was achieved by minimizing compound size through iterative structure-based optimization of a peptide iead. 185... 

A. Baici, P. Salgam, K. Fehr, and A. Boni. Inhibition of human elastase from polymorphonuclear leucocytes by a glycosaminoglycan polysulfate (Arteparon). Biochem. Pharmacol. 29 1723 (1980). 

Dialkylidenecephalosporin sulfones 92 are reported to be potent class C lactamase inhibitors <00T5709> and other cephalosporin sulfones show human elastase inhibiting abilities <00CHE1232, 01EJM185>. Many novel cephalosporins have been reported as a... 

Baici, A., Salgam, R, Fehr, K., Boni A. (1980) Inhibition of human elastase from PMN leucocytes by glycosaminoglycan polysulphate (arteparon). Biochemical Pharmacology, 29, 1723-1727. 

Oxo-4//-pyrido[],2-n]pyrimidin-2-yl]oxymethylsaccharin derivatives 418 exhibited human leukocyta elastase inhibitory activities (94EUP626378, 95USP5378720). 2-Substituted 4//-pyrido[l, 2-n]pyrimidin-4-one (419) is a potent human leukocyta elastase inhibitors (A", 1.79/xM) (96USP5512576). The 4//-pyrido[l,2-n]pyrimidin-4-one moiety was included in leukotriene antagonist 2-ethynylthiazole derivatives (98JAP(K) 98/195063)... 

Figure 15.6 Chromatogram of a plasma standard of human leukocyte elastase inhibitors obtained by using LC-LC. Adapted from Journal of Liquid Chromatography and Related Technologies, 19, R. A. Earley and L. R Tini, Versatile multidimensional chromatographic system for di ug discovery as exemplified by the analysis of a non-peptidic inhibitor of human leukocyte elastase , pp. 2527-2540, 1996, by courtesy of Marcel DekkeiTnc.

Adeyemi, E.O., Neumann, S., Chadwick, V.S., Hodgson, H.J.F. and Pepys, M.B. (1985). Circulating human leucocyte elastase in patients with inflammatory bowel disease. Gut 26, 1306-1311. 

HNE Human neutrophil elastase HNG Human neutrophil gclatinase (MMP-9)... 

Irreversible inhibition is probably due to the alkylation of a histidine residue.43 Chymotrypsin is selectively inactivated with no or poor inhibition of human leukocyte elastase (HLE) with a major difference the inactivation of HLE is transient.42,43 The calculated intrinsic reactivity of the coumarin derivatives, using a model of a nucleophilic reaction between the ligand and the methanol-water pair, indicates that the inhibitor potency cannot be explained solely by differences in the reactivity of the lactonic carbonyl group toward the nucleophilic attack 43 Studies on pyridyl esters of 6-(chloromethyl)-2-oxo-2//-1 -benzopyran-3-carboxylic acid (5 and 6, Fig. 11.5) and related structures having various substituents at the 6-position (7, Fig. 11.5) revealed that compounds 5 and 6 are powerful inhibitors of human leukocyte elastase and a-chymotrypsin thrombin is inhibited in some cases whereas trypsin is not inhibited.21... 

Finally, coumarin derivatives may act as general inhibitors of serine proteases or as specific inhibitors of human leukocyte elastase, depending on the nature of the substituents, through two distinct mechanisms, suicide substrates (a-chymotrypsin)... 

TABLE 11.1 Inhibition of a-Chymotrypsin and Human Leukocyte Elastase by Phenolic Esters of 6-(Chloromethyl)-2-oxo-2H-l-Benzopyran-3-Carboxylic Acid42... 

TABLE 11.2 Inhibition of Human Leukocyte Elastase, a-Chymotrypsin and Thrombin by 5 -Chloropyrid-3 -yl Derivatives at pH 8.0 and 25°C21... 

The acyl-enzyme can eliminate the 4-chlorine atom to generate this reactive intermediate that can then react with a nearby nucleophile such as His57 to give an alkylated acyl-enzyme derivative in which the inhibitor moiety is bound to the enzyme by two covalent bonds (Scheme 11.5). Inhibition is irreversible.59 The mechanism has been confirmed by X-ray structural analysis of protease-isocoumarin complexes. There is a cross-link between the inhibitor and the Serl95 and His57 residues of PPE.60 Human leukocyte elastase is also very efficiently inactivated.61... 

Human leukocyte elastase is a protease that degrades elastin and other connective tissue components. It is implicated in the pathogenesis of pulmonary emphysema and other inflammatory diseases such as rheumatoid arthritis and cystic fibrosis. Porcine pancreatic elastase has often been used as a model for HLE. Both enzymes have a small primary binding site Si. 

Doucet, C. Pochet, L. Thierry, N. Pirotte, B. Delarge, J. Reboud-Ravaux, M. 6-Substituted 2-OXO-2H-1 -benzopyran-3-carboxyI ic acid as a core structure for specific inhibitors of human leukocyte elastase. J. Med. Chem. 1999, 42, 4161—4171. 

Doucet, C. Vergely, I. Reboud-Ravaux, M. Guilhem, J. Kobaiter, R. Joyeau, R. Wakselman, M. Inhibition of human leucocyte elastase by functionalized V-aryl azeti-din-2-ones. Stereospecific synthesis and chiral recognition of disymmetrically C3-substi-tuted P-lactams. Tetrahedron Asymmetry 1997, 8, 739-751. 

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