Elastase, inhibitors

Bode, W., Papamokos, E., Musil, D. The high-resolution X-ray crystal structure of the complex formed between subtilisin Carlsberg and eglin c, an elastase inhibitor from the leech Hirudo medicinalis. Eur. J. Biochem. 166 (1987) 673-692... 

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.

There are other substrates for the E. coli Met(0) peptide reductase, one of which is Met(0)-a-l-PI. The native protein is the major serum elastase inhibitor that functions by forming a binary complex with elastase which inhibits its activity. Met(0)-a-l-PI, on the other hand, which can be formed by treatment of the protein with TV-chlorosuccinimide, cannot form a complex with elastase and therefore is not able to inhibit elastase activity117,118. Table 6 shows, however, that when Met(0)-a-l-PI is incubated in the presence of Met(0)-peptide reductase and dithiothreitol the protein regains its ability to form a complex with elastase and inhibit elastase activity119. Similar to results found with Met(0)-L12 reduced thioredoxin could replace the dithiothreitol as reductant in the enzymatic reaction. 

Further, Wasserman and coworkers developed a direct acylation of stabilized phosphonium ylides by carboxylic acids in presence of the EDCI/DMAP (way c). This last method allows the introduction of a-aminoacid structures into the resulting P-oxo phosphorus ylides [19-25],opening the way to the total synthesis of depsipeptide elastase inhibitors [22,24] or cyclic peptidic protease inhibitor EurystatinA [20]. 

Damage to connective caused by leakage of elastases leads to damage associated with inflammatory diseases, such as pulmonary emphysema, adult respiratory distress syndrome, septic shock, cystic fibrosis, carcinogenesis, chronic bronchitis, and rheumatoid arthritis. Compounds that directly inhibit elastase or its release from human neutrophils are of enormous pharmaceutical and cosmetological interest in the development of new anti-inflammatory drugs. A possible source for elastase inhibitors are the medicinal Asteraceae and Droseraceae, particularly those used as traditional medicine in Asia. 

Other potential elastase inhibitors based on the /3-lactam nucleus include cephem derivatives [64], penam derivatives [65], as well as novel bicyclic /3-lactams [66]. Monocyclic y-lactams (5.21) with appropriated substitution might also yield useful inhibitors [67]. 

Inflammatory cells produce profeases, which allow the cells to enter the affected area. Some pathogens also produce proteases in order to enter the body. Human milk contains active protease inhibitors (e.g., ot-1-antitr) sin, a-l-antichymotr) sin, and elastase inhibitor) that can limit the ability of pafhogens fo gain enfry info fhe body and limit the inflammation caused by the inflammatory response (Lindberg et al., 1982). 

Hlasta and Ackerman (72) reported a synthesis of the triazoles 379, related to the human leuokocyte elastase inhibitor WIN 62225 (380), based on an inter-molecular 1,3-dipolar cycloaddition of the azide 378 with alkynes (Scheme 9.72). They also investigated in detail the effect of steric and electronic factors on the regioselectivity of the cycloaddition reaction. (Azidomethyl)benzisothiazolone (378) underwent smooth 1,3-dipolar cycloaddition with various disubstituted acetylenes to give the corresponding triazoles (379) in 37-84% yields. Electron-deficient acetylenic dipolarophiles reacted more rapidly with the azide to give the respective triazoles. 

Protease 3D structural models elastase-inhibitor complex and drug design... 

One of the goals of synthetic medicinal chemistry is to design potent inilibitors of clinically important proteases. Elastase inhibitors may be useful for treatment of emphysema, pancreatitis, and arthritis,a/b while inhibitors of the angiotensinogen-converting enzyme or of renin (Box 22-D) can help control blood pressure. Inhibition of thrombin, factor Xa, or other blood clotting factors (Fig. 12-17) may prevent blood clots and inhibition of the cytosolic tryptase may provide a new treatment for asthma. Inhibition of the cysteine protease cathepsin K may help combat osteoporosis and inhibition of cysteine proteases of corona viruses may fight the common cold. Cysteine proteases of schistosomes are also targets for protease inhibitors.c... 

Fluorinated /1-Lactams and Biological Activities of /f-Lactamase and Elastase Inhibitors ... 

Roberts, B., Markland, W., Ley, A., Kent, R., White, D., Guterman, S., and Ladner, R. (1992) Directed evolution of a protein selection of potent neutrophil elastase inhibitors displayed on M13 fusion phage Proc Natl Acad Sci USA 89, 2429-2433. 

Inoue Y, Seiyama A, Tanaka H, Isao U, Akimau P, Nishino M, Shimazu T, Sugimoto H (2005) Protective effects of a selective neutrophil elastase inhibitor (sivelestat) on LSP-induced acute dysfunction of the pulmonary microcirculation. Crit Care Med 33(8) 1814-1822 Inoue Y, Tanaka H, Ogura H, Ukai I, Fujita K, Hosotsubo H, Shimazu T, Sugimoto H (2006) A neutrophil elastase inhibitor, sivelestat, improves leukocyte deformability in patients with acute lung injury. 1 Trauma 60(5) 936-943... 

Matem U, Schleberger C, Jelakovic S, Weckesser J, Schulz GE (2003) Binding Structure of Elastase Inhibitor Scyptolin A. Chem Biol 10 997... 

Torriglia, A., Perani, P., Borssas, J., Chaudun, E., Treton, J., Courtois, Y. and Counis, M.-F. (1998) L-DNasell, a molecule that links proteases and endonucleases in apoptosis, derives from the ubiquitous Serpin Leukocyte Elastase Inhibitor. Mol. Cell. Biol, 18, 3612-3619. 

This highly enantio- and diastereoselective organocatalytic /Mactam synthesis can be used, e.g., for preparation of pharmaceutically interesting products such as 43b. The formation of /Mactam 43b, which was investigated as an elastase inhibitor [62], proceeds with a diastereomeric ratio of 99 1 and an enantioselectivity of 99% ee (Scheme 5.28) [49, 52],... 

Cephalosporins in the sulfoxide or sulfone oxidation states can easily be obtained by treatment with different oxidants. This sulfur oxidation is usually accomplished for one of the following reasons (1) sulfoxide formation to obtain reactive intermediates for further transformations (2) sulfoxide formation with subsequent reduction in cephems to shift the double bond from position 2 to position 3 (3) preparation of sulfones as /3-lactamase or elastase inhibitors. 

Hie therapeutic need for potent inhibitors of elastase has been recognized by several pharmaceutical companies. Administration of proteinase inhibitors to augment the normal endogenous levels should shift the balance in tile direction of the inhibitor. One approach is the replacement or supplementation with natural or recombinant raOtemacenuii elastase inhibitors r7 81. A secruid anomach is the... 

M- Sponei, H. Nick, and H. P. Schnebli. Different susceptibility of elastase inhibitors to inactivation by proteioases from Staphylococcus aureus and Pseudomonas aeruginosa. Biol Chan. Hoppe-Seyler 372 963 (1991). 

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