Synthesis, stability, biochemical and pharmacokinetic properties of a new potent and selective 4-oxo-β-lactam inhibitor of human leukocyte elastase

Mulchande, Jalmira; Simões, Sandra; Gaspar, Maria Manuela; Eleutério, Carla; Oliveira, Rudi; Cruz, M.E.M.; Moreira, Rui; Iley, Jim

doi:10.3109/14756366.2010.486794

Cited by 9 publications

(8 citation statements)

References 26 publications

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“…Furthermore, these studies indicated that a diethyl substitution in the 4-oxo-β-lactam scaffold, along with N-phenyl derivatization of this structure, selectively improved the activity against HNE [24]. Accordingly, previous studies reported by our group [24][25][26] also showed that these compounds could be quite promising regarding the inhibition of serine proteases. In particular, ER143 (1) [21] showed high potency and selectivity for HNE but it presented poor solubility and cell viability when tested in immortalized human keratinocyte (HaCaT) cells [21].…”

Section: Introductionmentioning

confidence: 90%

Novel and Modified Neutrophil Elastase Inhibitor Loaded in Topical Formulations for Psoriasis Management

et al. 2020

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Human neutrophil elastase (HNE) is a serine protease that degrades matrix proteins. An excess of HNE may trigger several pathological conditions, such as psoriasis. In this work, we aimed to synthesize, characterize and formulate new HNE inhibitors with a 4-oxo-β-lactam scaffold with less toxicity, as well as therapeutic index in a psoriasis context. HNE inhibitors with 4-oxo-β-lactam scaffolds were synthesized and characterized by NMR, FTIR, melting point, mass spectrometry and elemental analysis. In vitro cytotoxicity and serine protease assays were performed. The compound with the highest cell viability (AAN-16) was selected to be incorporated in an emulsion (AAN-16 E) and in a microemulsion (AAN-16 ME). Formulations were characterized in terms of organoleptic properties, pH, rheology, droplet size distribution, in vitro drug release and in vivo psoriatic activity. All compounds were successfully synthesized according to analytical methodology, with good yields. Both formulations presented suitable physicochemical properties. AAN-16 E presented the most promising therapeutic effects in a murine model of psoriasis. Overall, new HNE inhibitors were synthesized with high and selective activity and incorporated into topical emulsions with potential to treat psoriasis.

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Section: Introductionmentioning

confidence: 90%

Novel and Modified Neutrophil Elastase Inhibitor Loaded in Topical Formulations for Psoriasis Management

et al. 2020

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“…Substituted azetidine-2, 4-diones 6 have been shown to be highly potent and selective inhibitors of HNE (86–87). Optimal inhibitory activity was observed with R 1 = R 2 = ethyl and R 3 = N 1 -aryl moiety having a heteroarylthiomethyl group at the para position.…”

Section: Hne Inhibitorsmentioning

confidence: 99%

Neutrophil elastase inhibitors

Groutas

Dou

Alliston

2011

Expert Opinion on Therapeutic Patents

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Introduction Chronic obstructive pulmonary disease (COPD) constitutes a worldwide health problem. There is currently an urgent and unmet need for the development of small molecule therapeutics capable of blocking and/or reversing the progression of the disorder. Recent studies have greatly illuminated our understanding of the multiple pathogenic processes associated with COPD. Of paramount importance is the key role played by proteases, oxidative stress, apoptosis, and inflammation. Insights gained from these studies have made possible the exploration of new therapeutic approaches. Areas covered An overview of major developments in COPD research with emphasis on low molecular weight neutrophil elastase inhibitors is described in this review. Expert opinion Great strides have been made toward our understanding of the biochemical and cellular events associated with COPD. However, our knowledge regarding the inter-relationships among the multiple pathogenic mechanisms and their mediators involved is till limited. The problem is further compounded by the unavailability of suitable validated biomarkers for assessing the efficacy of potential therapeutic interventions. The complexity of COPD suggests that effective therapeutic interventions may require the administration of more than one agent such as, for instance, an HNE or MMP-12 inhibitor with an anti-inflammatory agent such as a phosphodiesterase-4 inhibitor, or a dual function agent capable of disrupting the cycle of proteolysis, apoptosis, inflammation and oxidative stress

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“…The 4-oxo-β-lactams are selective acylating irreversible NE inhibitors. A new 4-oxo-β-lactam containing a N -(4-(phenylsulphonylmethyl)phenyl) group was proposed as a potent slow-tight binding NE inhibitor, showing also selectivity for proteinase 3 and cathepsin G; however, it presents weak stability, due to off-target reactions with plasma and liver enzymes 84 . The design of small-molecule activity-based probes by click chemistry approach on 4-oxo-β-lactams was also reported as an efficient tool for the development of new potent NE inhibitors; these probes showed adequate fluorescence properties, and neutrophil internalization, suitable for detection of NE, making them a promise as diagnostic tools 85 .…”

Section: Exogenous and Therapeutic Neutrophil Serine Protease Inhibitmentioning

confidence: 99%

Neutrophil Elastase Inhibitors and Chronic Kidney Disease

Bronze-da-Rocha¹,

Santos-Silva²

2018

Int. J. Biol. Sci.

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End-stage renal disease (ESRD), the last stage of chronic kidney disease (CKD), is characterized by chronic inflammation and oxidative stress. Neutrophils are the front line cells that mediate an inflammatory response against microorganisms as they can migrate, produce reactive oxygen species (ROS), secrete neutrophil serine proteases (NSPs), and release neutrophil extracellular traps (NETs). Serine proteases inhibitors regulate the activity of serine proteases and reduce neutrophil accumulation at inflammatory sites. This review intends to relate the role of neutrophil elastase in CKD and the effects of neutrophil elastase inhibitors in predicting or preventing inflammation.

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Synthesis, stability, biochemical and pharmacokinetic properties of a new potent and selective 4-oxo-β-lactam inhibitor of human leukocyte elastase

Cited by 9 publications

References 26 publications

Novel and Modified Neutrophil Elastase Inhibitor Loaded in Topical Formulations for Psoriasis Management

Novel and Modified Neutrophil Elastase Inhibitor Loaded in Topical Formulations for Psoriasis Management

Neutrophil elastase inhibitors

Neutrophil Elastase Inhibitors and Chronic Kidney Disease

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