Design, synthesis and antithrombotic evaluation of novel dabigatran etexilate analogs, a new series of non-peptides thrombin inhibitors

Chen, Dongxing; Wang, Shaochi; Diao, Xiao-Juan; Zhu, Qihua; Shen, Hui-liang; Han, Xiaoyang; Wang, Yiwei; Gong, Guoqing; Xu, Yungen

doi:10.1016/j.bmc.2015.10.036

Cited by 5 publications

(2 citation statements)

References 20 publications

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“…Although serine proteases are responsible for several physiological functions in humans, abnormal and excessive levels can cause or promote disease 28 29 . Recent experimental and clinical studies have shown that enhanced HNE activity is associated with the degradation of elastin-rich proteins in the pathological progression of ALI.…”

Section: Discussionmentioning

confidence: 99%

Ilex kaushue and Its Bioactive Component 3,5-Dicaffeoylquinic Acid Protected Mice from Lipopolysaccharide-Induced Acute Lung Injury

Chen

Hwang

et al. 2016

Sci Rep

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Acute lung injury (ALI) is a severe respiratory disease with high mortality rates worldwide. Recent reports suggest that human neutrophil elastase (HNE) plays a key role in the inflammatory response that is characteristic of ALI, which indicates that the development of HNE inhibitors could be an efficient treatment strategy. In the current study, an enzyme-based screening assay was used to identify effective HNE inhibitors from a number of traditional Chinese medicines (TCMs). Among them, a water extract of Ilex kaushue (IKWE) effectively inhibited HNE activity (IC50, 11.37 ± 1.59 μg/mL). Using bioactivity-guided fractionation, one new compound and 23 known compounds were identified. Compound 6 (identified as 3,5-dicaffeoylquinic acid; 3,5-DCQA) exerted the most potent and selective inhibitory effect on HNE activity (IC50, 1.86 ± 0.06 μM). In a cell-based assay, 3,5-DCQA not only directly reduced superoxide generation and elastase activity but also attenuated the Src family kinase (SRKs)/Vav signaling pathway in N-formyl-L-Met-L-Leu-L-Phe (fMLF)-stimulated human neutrophils. In an animal disease model, both 3,5-DCQA and standardized IKWE protected against lipopolysaccharide-induced ALI in mice, which provides support for their potential as candidates in the development of new therapeutic agents for neutrophilic inflammatory diseases.

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Section: Discussionmentioning

confidence: 99%

Ilex kaushue and Its Bioactive Component 3,5-Dicaffeoylquinic Acid Protected Mice from Lipopolysaccharide-Induced Acute Lung Injury

Chen

Hwang

et al. 2016

Sci Rep

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“…Molecular docking studies have found that compound 12a interacts with Asp36, His102, Trp53 and Tyr101 to form hydrogen bonds with thrombin active site. Based on bioisosteric and scaffold hopping principles, Chen et al [29] synthesized two dabigatran mimics (13a and 14), and in vitro antithrombotic efficacy study showed that both 13a (IC50: 9.20 nM) and 14 (IC50: 7.48 nM) had excellent anticoagulant effect (Fig. 14).…”

Section: Dabigatran Derivativesmentioning

confidence: 99%

Progress of thrombus formation and research on the structure-activity relationship for antithrombotic drugs

Guo

Qian

et al. 2022

European Journal of Medicinal Chemistry

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Design, synthesis and antithrombotic evaluation of novel non-peptide thrombin inhibitors

Chen

Shi

Liu

et al. 2017

Bioorganic & Medicinal Chemistry

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Design, synthesis and antithrombotic evaluation of novel dabigatran etexilate analogs, a new series of non-peptides thrombin inhibitors

Cited by 5 publications

References 20 publications

Ilex kaushue and Its Bioactive Component 3,5-Dicaffeoylquinic Acid Protected Mice from Lipopolysaccharide-Induced Acute Lung Injury

Ilex kaushue and Its Bioactive Component 3,5-Dicaffeoylquinic Acid Protected Mice from Lipopolysaccharide-Induced Acute Lung Injury

Progress of thrombus formation and research on the structure-activity relationship for antithrombotic drugs

Design, synthesis and antithrombotic evaluation of novel non-peptide thrombin inhibitors

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