β-Sultams—A novel class of serine protease inhibitors

Beardsell, Mark; Hinchliffe, Paul S.; Wood, J. Matthew; Wilmouth, R.C.; Schofield, Christopher J.; Page, Michael I.

doi:10.1039/b100294p

Cited by 29 publications

(34 citation statements)

References 14 publications

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“…β-Sultams also have the potential to act as peptide mimics and as transition state analogues of the tetrahedral intermediates formed in many acyl transfer reactions [4]. The mechanism of its action has been studied with experimental [2][3][4][5][6][7][8] and theoretical [9][10][11] methods.…”

Section: Introductionmentioning

confidence: 99%

Theoretical Study for Alcoholysis of N-Benzyl 3-Oxo-?-Sultam

Feng

et al. 2005

Struct Chem

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The alcoholysis mechanisms of N-benzyl 3-oxo-β-sultam are investigated at B3LYP/6-31G * level. Different possible mechanistic pathways of the reaction are proposed. The results show that the cleavage of S N bond producing P1 has a little lower energy barrier than does C N bond producing P2. The inclusion of solvent effects by a polarizable continuum model (PCM) does not change the conclusions based on the gas-phase study.

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Section: Introductionmentioning

confidence: 99%

Theoretical Study for Alcoholysis of N-Benzyl 3-Oxo-?-Sultam

Feng

et al. 2005

Struct Chem

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“…There is X-ray crystallographic evidence for the sulfonylation of the active site serine of elastase inactivated by b-sultams. 13 Non-covalent binding of one equivalent of the ring opened hydrolysis product of 2 would lead to a mass difference of +228. Enzyme inactivation is irreversible and there is no return of enzyme activity over 4 days.…”

Section: Resultsmentioning

confidence: 99%

Novel mechanism of inhibiting β-Lactamases by sulfonylation using β-Sultams

Page

Hinchliffe

Wood

et al. 2003

Bioorganic & Medicinal Chemistry Letters

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“…Hence, β‐sultam 24 (Fig. ) was found to inhibit PPE with a second order rate constant for inactivation, K i , of 4 M −1 s −1 at pH 7 …”

Section: Acylating Inhibitorsmentioning

confidence: 95%

Targeting COPD: advances on low‐molecular‐weight inhibitors of human neutrophil elastase

Lucas

Costa

Guedes

et al. 2011

Medicinal Research Reviews

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Chronic obstructive pulmonary disease (COPD) is a major increasing health problem and the World Health Organization (WHO) reports COPD as the fifth leading cause of death worldwide. COPD refers to a condition of inflammation and progressive weakening of the structure of the lung as well as irreversible narrowing of the airways. Current treatment is only palliative and no available drug halts the progression of the disease. Human neutrophil elastase (HNE) is a serine protease, which plays a major role in the COPD inflammatory process. The protease/anti-protease imbalance leads to an excess of extracellular HNE hydrolyzing elastin, the structural protein that confers elasticity to the lung tissue. Although HNE was identified as a therapeutic target for COPD more than 30 years ago, only Sivelestat (ONO-5046), an HNE inhibitor from Ono Pharmaceutical, has been approved for clinical use. Nevertheless, Sivelestat is only approved in Japan and its development in the USA was terminated in 2003. Other inhibitors in pre-clinical or phase I trials were discontinued for various reasons. Hence, there is an urgent need for low-molecular-weight synthetic elastase inhibitors and the present review discusses the recent advances on this field covering acylating agents, transition-state inhibitors, mechanism-based inhibitors, relevant natural products, and major patent disclosures.

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β-Sultams—A novel class of serine protease inhibitors

Cited by 29 publications

References 14 publications

Theoretical Study for Alcoholysis of N-Benzyl 3-Oxo-?-Sultam

Theoretical Study for Alcoholysis of N-Benzyl 3-Oxo-?-Sultam

Novel mechanism of inhibiting β-Lactamases by sulfonylation using β-Sultams

Targeting COPD: advances on low‐molecular‐weight inhibitors of human neutrophil elastase

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