Human neutrophil elastase inhibitor

Utility Human Neutrophil Elastase Inhibitor in the Treatment of... 

Shi, Y., and Sharma, S. (1999) Metallopep-tide approach to the design of biologically active ligands Design of specific human neutrophil elastase inhibitors. Bioorg. Med. Chem. Lett. 9, 1469-1474. 

Nitrogen heterocycles can be accessed by the same reductive cyclization strategy [75]. Modest yields of the desired products are obtained in these reactions (Eq. 64), which serve as intermediates in the synthesis of human neutrophil elastase inhibitors. 

Shintani, T. Takamoto, M. Sawada, M. Aishita, H. Nakagawa, T. Simultaneous determination of human neutrophil elastase inhibitor (ONO-5046) and its metabolite in plasma and urine by direct injection column-switching HPLC, J.Pharm.BiomedAnal., 1994,12, 397-405. 

To avoid the problems with kinetic control of a reaction during peptide bond formation, it is recommended that longer peptide phosphonates be synthesized stepwise by extension in the N-terminal direction, starting with diphenyl l-(aminoalkyl)phosphonates. The longer coupling time will provide peptide products that are usually an equivalent (or close to equivalent) mixture of diastereomers. The synthesis of longer peptides is demonstrated by the synthesis of Boc-Val-Pro-Valp(OPh)2, which is an excellent inhibitor of human neutrophil elastase (kobs/[I] = 27,000 M 1s 1)J38 ... 

We have extended these studies to five /V-bcnzoylazolcs (imidazole, pyrazole, indole, benzimidazole and carbazole) [35] but this time centered on crystallography and solid state NMR. 9-Benzoylcarbazole (29) has a low barrier (29.7 kJ mol1) and shows spontaneous resolution (both axial enantiomers were separated by crystallization). Recently, /V-benzoylpyrazoles have been described as inhibitors of human neutrophil elastase [36],... 

Diazetidin-2,4-dione has been found to be a chymase inhibitor (IC50 4.0nM). It has been found that 1,3-diazetidin-2,4-dione derivatives possess high activities against bovine pancreatic cr-chrymotrypsin, human cathepsin G, and human neutrophil elastase. Some of the derivatives of l,3-diazetidin-2,4-diones have been shown to be effective as a scaffold for serine protease inhibitors <2001BML1691>. Further, 1,3-diazetidinone containing scaffolds have been found to possess potential antibacterial properties (Section 2.13.7.3). 

E. C. Luccy, P. J. Stone. D. EL Ciccolclla, R. Bcuer, T. 0. Christensen, R. C. Thompson, and G- L. Snider. Recombinant human secretory leukocyte-protease inhibitor in vitro properties, and amelioration of human neutrophil elastase-induced emphysema and secretory cell metaplasia in the hamster. /. Lab. Clin. hied. 7/5 224... 

C. P. Dom, and K, HoogSteen. Structure of human neutrophil elastase in complex with a peptide diloramethyl ketone inhibitor at 134 A resolution. Proc. NatL Sci. USA 86 7 (im). 

Charlton J, Sennello J, Smith D, In vivo imaging using an aptamer inhibitor of human neutrophil elastase, Chem. Biol., 4 809-816, 1997. 

Gleeson MP, IH Hillier, NA Burton (2004) Theoretical analysis of peptidyl alpha-ketoheterocyclic inhibitors of human neutrophil elastase Insight into the mechanism of inhibition and the application of QM/MM calculations in structure-based drug design. Organic Biomolecular Chemistry 2 (16) 2275-2280... 

Edwards PD, Zottola MA, Davis M et al (1995) Peptidyl alpha-ketoheterocyclic inhibitors of human neutrophil elastase. In vitro and in vivo potency of a series of peptidyl alpha-ketobenzoxazoles. J Med Chem 38 3972-3982... 

Took, J.M.S.L.L Macedo, L.LP. Moura, G.E.D.D. Teixeira, F.M. Oliveira, A.S. Queiroz, A.F.S. Sales, M.P. A serine proteinase inhibitor isolated from Tamarindus indica seeds and its effects on the release of human neutrophil elastase. Life Sciences. 2005, 76,2881-2891. 

Peet, N.P. Burkhart, J.P. Angelastro, M.R. Giroux, E.L. Mehdi, S. Bey, P. Kolb, M. Neises, B. and Schirlin, D. Synthesis of peptidyl fluoromethyl ketones and peptidyl alpha-keto esters as inhibitors of porcine pancreatic elastase, human neutrophil elastase, and rat and human neutrophil cathepsin G. J Med Chem 33(l) 394-407, 1990. 

Imaki, K., Okada, T., Nakayama, Y., Nagao, Y, Kobayashi, K., Sakai, Y., Mohri, T., Amino, T., Nakai, H., Kawamura, M. Non-pep-tidic inhibitors of human neutrophil elastase the design and synthesis of sulfonanilide-containing inhibitors. Bioorg. Med. Chem. 1996, 4,2115-2134. 

A. Rudolphus, R. Heinzel-Wieland, V. A. M. M. Vincent, D. Saunders, G. J. Steffens, J. H. Dijkman, and J. A Kramps. Oxidation-resistant variants of recombinant antileucoprotease are better inhibitors of human-neutrophil-elastase-induced emphysema in hamsters than natural recombinant antileukoprotease. Clin. Sci. 81 777 (1991). 

Smith, D. and G. P. Kirschenheuter, et al. (1995). In vitro selection of RNA-based irreversible inhibitors of human neutrophil elastase. Chem Bioll, 741-750... 

Siehczyk and co-workers have presented the synthesis and the measurement of the inhibitory activity of novel peptidyl derivatives of a-aminoalkylphosphonate diaryl esters (449) as human neutrophil elastase (HNE) inhibitors. Their selectivity against other serine proteases, including porcine pancreatic elastase, chymotrypsin, and trypsin, has also been demonstrated. The compound (450) displayed the best balance of high inhibitory activity against HNE and selectivity for HNE over porcine... 

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