Chronic obstructive pulmonary disease, characterised by a slowly progressive, irreversible airways limitation, is a major worldwide cause of chronic morbidity and mortality. The imbalance between human neutrophil elastase and endogenous antiproteases may cause excess human neutrophil elastase in pulmonary tissues, which may be considered a major pathogenic factor in chronic obstructive pulmonary disease. Great effort has been devoted to finding a method to restore the balance, resulting in the discovery of potent two-typed small-molecular-weight human neutrophil elastase inhibitors. In the application of chronic obstructive pulmonary disease therapy, the human neutrophil elastase inhibitors mainly focused upon include ONO-5046, MR-889, L-694,458, CE-1037, GW-311616 and TEI-8362 as the acyl-enzyme inhibitors; and ONO-6818, AE-3763, FK-706, ICI-200,880, ZD-0892 and ZD-8321 as the transition-state inhibitors. In this review, various problems that remain to be solved in the clinical use of human neutrophil elastase inhibitors are discussed.

01 Jun 1997·Journal of Medicinal ChemistryQ1 · MEDICINE

Discovery and Biological Activity of Orally Active Peptidyl Trifluoromethyl Ketone Inhibitors of Human Neutrophil Elastase

Q1 · MEDICINE

Article

Author: Tuthill, Paul A. ; Trainor, Diane A. ; Edwards, Philip D. ; Veale, Chris A. ; Lewis, Joseph J. ; Strimpler, Ann ; Wildonger, Richard A. ; Zottola, Mark ; Williams, Joseph C. ; Rakiewicz, Donna ; Wolanin, Donald J. ; Ewing, Barbara ; Steelman, Gary ; Andisik, Donald W. ; Mauger, Russell C. ; Bryant, Craig A. ; Gomes, Bruce

Previously we had shown that tripeptidyl trifluoromethyl ketones (TFMKs) possessing an N-terminal diarylacylsulfonamide, such as ICI 200,880 and ICI 200,355, displayed unparalleled protection against the lung damage induced by human neutrophil elastase (HNE) when the inhibitors were administered intratracheally. Since the diarylacylsulfonamides were designed specifically to afford a long residence time in the lung, it was not unexpected that inhibitors from this class of TFMKs were not active when administered orally. Upon evaluating a large number of peptidyl TFMKs possessing a variety of N-terminal groups, several compounds were identified which demonstrated oral activity. Compounds were evaluated for their oral activity by measuring their ability to inhibit the increase in lung weight relative to body weight (Lw/Bw), the increase in red blood cells, and the increase in white blood cells induced by intratracheally administered HNE (100 micrograms/hamster). A number of tripeptidyl trifluoromethyl ketones containing neutral N-terminal groups displayed good oral activity, while those containing basic, acidic, or polar groups did not. Compound 50, possessing an N-terminal 4-(CH3O)C6H4CO group, was particularly effective, reducing Lw/Bw by 77%, red cells by 89%, and white cells by 91% when dosed at 37.5 mg/kg orally. Thus, by modifying the N-terminal group of tripeptidyl TFMKs, inhibitors can be designed which are effective in vivo when administered either orally or intratracheally.

01 Jun 1997·Journal of Medicinal ChemistryQ1 · MEDICINE

Dual Inhibition of Human Leukocyte Elastase and Lipid Peroxidation: In Vitro and in Vivo Activities of Azabicyclo[2.2.2]octane and Perhydroindole Derivatives

Q1 · MEDICINE

Article

Author: Portevin, Bernard ; Lonchampt, Michel ; De Nanteuil, Guillaume ; Canet, Emmanuel

A series of potent and selective human leukocyte elastase (HLE) inhibitors of the Val-Pro-Val type has been developed. Initially, the central proline residue was replaced by nonnatural amino acids Phi ((2S,3aS,7aS)-perhydroindole-2-carboxylic acid) and Abo ((3S)-2-azabicyclo-[2.2.2]octane-3-carboxylic acid), and secondly several groups able to confer antioxidant properties to the molecule were introduced at the lipophilic N-terminal side chain. When compared to reference inhibitors, in vitro HLE inhibitory potency was maintained (10-100 nM) both with compounds containing the antioxidant moiety at the end of the N-terminal side chain and with compounds in which the N-terminal valine of the tripeptidic sequence had been replaced by a epsilon-substituted lysine. The lipidic peroxidation inhibitory potency of this series of inhibitors was found to be similar to that of the reference antioxidant compounds (around 1 microM). Moreover, HLE-induced hemorrhage in the hamster lung was effectively prevented (40-60% at 15 micrograms/kg) by most of the inhibitors tested when administered intratracheally 3 h before instillation of elastase. Among the most active analogs, compounds 11a,c,g were still active when administered 18 h before elastase. Interestingly, compound 14a was able to prevent HLE-mediated lung damage when administered 72 h prior to enzymatic challenge, indicating exceptional stability and retention in the lung. Finally, in a 14-day chronic model of emphysema in the hamster, 14a significantly conserved alveolar spaces, a marker of lung tissue destruction, and was more potent than reference inhibitor ICI 200 880. This indicates that addition of peroxidation inhibitory properties to an HLE inhibitor can provide a powerful in vivo inhibitor of pulmonary tissue destruction.

100 Deals associated with ICI-200880

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Indication	Highest Phase	Country/Location	Organization	Date
Cystic Fibrosis	Phase 2	GB	AstraZeneca PLC	-
Myocardial Ischemia	Phase 2	GB	AstraZeneca PLC	-
Myocardial Ischemia	Phase 2	-	AstraZeneca Pharmaceuticals Co. Ltd.	-
Pulmonary Emphysema	Phase 2	-	AstraZeneca Pharmaceuticals Co. Ltd.	-
Pulmonary Emphysema	Phase 2	US	AstraZeneca PLC	-
Pulmonary Emphysema	Phase 2	EU	-	-
Respiratory Distress Syndrome, Adult	Phase 2	US	AstraZeneca PLC	-
Respiratory Distress Syndrome, Adult	Phase 2	EU	-	-
Respiratory Distress Syndrome, Newborn	Phase 2	-	AstraZeneca Pharmaceuticals Co. Ltd.	-

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