Design and Synthesis of Peptide-Based Carboxylic Acid-Containing Transition-State Inhibitors of Human Neutrophil Elastase

Sato, Fuminori; Inoue, Yuriko; Omodani, Tomoki; Imano, Kiyomi; Okazaki, Hiroshi; Takemura, Tadashi; Komiya, M

doi:10.1016/s0960-894x(01)00797-1

Cited by 9 publications

(5 citation statements)

References 9 publications

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“…For analysis of the NSP activities, cell lysates were added to 384well plates together with DMSO control (to measure activity within the sample) or protease inhibitors (to confirm that the measured activity was due to NE, Pr3, and CatG, respectively). The inhibitors used were compound 4 21 (AstraZeneca) for DPP1, AZD9668 33 (AstraZeneca) for NE, sivelestat 34 for Pr3, and cathepsin G inhibitor I (Merck Millipore) for CatG. Synthetic peptide substrates (methoxysuccinyl-Ala-Ala-Pro-Val-AMC (Sigma) for NE, aminobenzoyl-Val-Ala-Asp-Cys-Ala-Asp-Gln-ethylenediamine 2,4-dinitrophenyl (Peptide Synthetics) for Pr3, and N-succinyl-Ala-Ala-Pro-Phe-pNA (Sigma) for CatG) were added before plates were read using a Tecan Safire plate reader (Tecan Group Ltd., Switzerland).…”

Section: ■ Associated Contentmentioning

confidence: 99%

Discovery of Second Generation Reversible Covalent DPP1 Inhibitors Leading to an Oxazepane Amidoacetonitrile Based Clinical Candidate (AZD7986)

et al. 2016

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Section: ■ Associated Contentmentioning

confidence: 99%

Discovery of Second Generation Reversible Covalent DPP1 Inhibitors Leading to an Oxazepane Amidoacetonitrile Based Clinical Candidate (AZD7986)

et al. 2016

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“…[160] Sato andc o-workersf ound compound 116 as ap otent inhibitor of HNE (IC 50 = 0.033 mm)a nd had excellent in vivo activity against HNE-induced lung hemorrhage in hamsters ( Figure 49). [161] Melatonin is ah ormone that exerts multiple actions mainly through two G-protein-coupled receptors, MT 1 and MT 2 .D esigning selective agonists or antagonists of these receptors could be useful to treat depression, insomnia, and circadian rhythmd ysfunction. [162] Compound 117 was synthesized by Sun and co-workers and was found to have better affinity for the MT 1 and MT 2 receptors than melatonin itself ( Figure 50).…”

Section: Other Therapeutic Targetsmentioning

confidence: 99%

Recent Advances in the Development of Pharmacologically Active Compounds that Contain a Benzoxazole Scaffold

et al. 2015

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In recenty ears, the emergence of biologically active compounds that contain ah eterocyclic ring has gained ag reat deal of attention among medicinal chemists. Among these, benzoxazole-based compounds are particularly attractive because of their wide range of pharmacological activities. In this focus review, we highlight recent advancements in the development of benzoxazole-based pharmacologically active compounds since the year 2000.

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“…Dainippon Pharmaceutical decided to introduce a substituent on the benzoxazole ring to achieve better fitting to the S1′ HNE subsite and they evaluated a new series of peptide‐based carboxylic acid containing HNE inhibitors . However, after lead optimization this company came up with compound AE‐3763 ( 35 , Fig.…”

Section: Transition State Analogsmentioning

confidence: 99%

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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Design and Synthesis of Peptide-Based Carboxylic Acid-Containing Transition-State Inhibitors of Human Neutrophil Elastase

Cited by 9 publications

References 9 publications

Discovery of Second Generation Reversible Covalent DPP1 Inhibitors Leading to an Oxazepane Amidoacetonitrile Based Clinical Candidate (AZD7986)

Discovery of Second Generation Reversible Covalent DPP1 Inhibitors Leading to an Oxazepane Amidoacetonitrile Based Clinical Candidate (AZD7986)

Recent Advances in the Development of Pharmacologically Active Compounds that Contain a Benzoxazole Scaffold

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

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