Synthesis and Characterization of Human Neutrophil Elastase Inhibitors Derived from Aromatic Esters of Phenylalkanoic Acids

Gp, Kirschenheuter; Oleksyszyn, Józef; Lw, Spruce; Wieczorek, Maciej; Tm, Kloppel; Simon, Horst D.; Jc, Cheronis

doi:10.1007/978-3-0348-7397-0_6

Cited by 3 publications

(3 citation statements)

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“…Among them, the most advanced is the sulfonamide derivative ONO-5046 (silvistat), 57 a pivaloyl ester acylating agent, 47 registered in Japan for the treatment of ARDS and septic shock. Another compound in Phase II studies for ARDS and cystic fibrosis is CE-1037 58, 48 whereas the GlaxoWellcome 5,5-trans-b-lactam derivative 59 (GW-311616) is in Phase I trials for OPD. 44 Functionalized sulfonamides coupled with 1,2,5-thiadizolidin-3-one 1,1-dioxide scaffolds of type 60 were also recently shown to act as potent inhibitors of several serine proteases, including the enzyme of interest in this section.…”

Section: H U M a N N E U T R O P H Y L E L A S T A S E S U L F O N mentioning

confidence: 99%

“…21 Since both MMPs and TACE contribute synergistically to the pathophysiology of many diseases, such as arthritis, bacterial meningitis, tumor invasion, etc., the dual inhibition of these enzymes emerged as an interesting target for the drug design and many such compounds have been reported ultimately. [38][39][40][41][42][43] A large series of acetylenic a-amino acid-based sulfonamide hydroxamic acid and mercaptan derivatives (of types [45][46][47][48] and their use as inhibitors of TACE and for the treatment of rheumatoid arthritis, graft rejection, cachexia, inflammation, fever, insulin resistance, septic shock, congestive heart failure, inflammatory bowel disease, HIV infection, or inflammatory diseases of the central nervous system, were recently reported. 35 The inhibitory activity against MMP-1, MMP-9, MMP-13, and TACE of these compounds was also investigated in vitro.…”

Section: T a C E I N H I B I T O R S O F T H E S U L F O N A M I D mentioning

confidence: 99%

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Protease inhibitors of the sulfonamide type: Anticancer, antiinflammatory, and antiviral agents

Supuran

Casini

Scozzafava

2003

Medicinal Research Reviews

395

153

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The sulfonamides constitute an important class of drugs, with several types of pharmacological agents possessing antibacterial, anticarbonic anhydrase, diuretic, hypoglycemic, and antithyroid activity among others. A large number of structurally novel sulfonamide derivatives have ultimately been reported to show substantial protease inhibitory properties. Of particular interest are some metalloprotease inhibitors belonging to this class, which by inhibiting several matrix metalloproteases (MMPs) show interesting antitumor properties. Some of these compounds are currently being evaluated in clinical trials. The large number of sulfonamide MMP inhibitors ultimately reported also lead to the design of effective tumor necrosis factor-alpha converting enzyme (TACE) inhibitors, potentially useful in the treatment of inflammatory states of various types. Since both MMPs and TACE contribute synergistically to the pathophysiology of many diseases, such as arthritis, bacterial meningitis, tumor invasion; the dual inhibition of these enzymes emerged as an interesting target for the drug design of anticancer/antiinflammatory drugs, and many such sulfonamide derivatives were recently reported. Human neutrophyl elastase (HNE) inhibitors of the sulfonamide type may also be useful in the treatment of inflammatory conditions, such as emphysema, cystic fibrosis, chronic bronchitis, ischemia reperfusion injury, and acute respiratory distress syndrome. Inhibition of some cysteine proteases, such as several caspase and cathepsin isozymes, may lead to the development of pharmacological agents effective for the management of several diseases, such as rheumatoid arthritis, inflammatory bowel disease, brain damage, and stroke. Another research line that progressed much in the last time regards different sulfonamides with remarkable antiviral activity. Some clinically used HIV protease inhibitors (such as amprenavir) possess sulfonamide moieties in their molecules, which are critical for the potency of these drugs, as shown by means of X-ray crystallography, whereas a very large number of other derivatives are constantly being synthesized and evaluated in order to obtain compounds with lower toxicity or augmented activity against viruses resistant to the such first generation drugs. Other viral proteases, such as those isolated from several types of herpes viruses may be inhibited by sulfonamide derivatives, leading thus to more effective classes of antiviral drugs.

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Section: H U M a N N E U T R O P H Y L E L A S T A S E S U L F O N mentioning

confidence: 99%

Section: T a C E I N H I B I T O R S O F T H E S U L F O N A M I D mentioning

confidence: 99%

Protease inhibitors of the sulfonamide type: Anticancer, antiinflammatory, and antiviral agents

Supuran

Casini

Scozzafava

2003

Medicinal Research Reviews

395

153

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“…Few compounds appear in the literature with this dual inhibitory capacity. CT-1037 ( 2 ) is described as a potent elastase inhibitor (IC 50 = 3 nM) embedded with an oxidative activation feature, and P 1517 ( 3 ) is given as an elastase inhibitor with an IC 50 on HLE around 0.1 mM but with in vivo radical scavenger properties superior to N -acetylcysteine …”

Section: Introductionmentioning

confidence: 99%

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

et al. 1997

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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.

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Chapter 20. Proteinases in Inflammation

Krantz

1993

Annual Reports in Medicinal Chemistry

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Synthesis and Characterization of Human Neutrophil Elastase Inhibitors Derived from Aromatic Esters of Phenylalkanoic Acids

Cited by 3 publications

References 8 publications

Protease inhibitors of the sulfonamide type: Anticancer, antiinflammatory, and antiviral agents

Protease inhibitors of the sulfonamide type: Anticancer, antiinflammatory, and antiviral agents

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

Chapter 20. Proteinases in Inflammation

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