4.7 Article

Non-peptidyl non-covalent cathepsin C inhibitoEEr bearing a unique thiophene-substituted pyridine: Design, structure-activity relationship and anti-inflammatory activity in vivo

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ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2022.114368

关键词

Cathepsin C; Inhibitors; Metabolic stability; Anti-inflammatory activity

资金

  1. Natural Science Foundation of China [21977001]

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In this study, a novel Cat C inhibitor SF38 was identified through structure-based design and modification. SF38 exhibited strong inhibitory activity against Cat C, showed anti-inflammatory effects, and had acceptable PK properties.
Cathepsin C (Cat C) is involved in inflammation regulation by activating neutrophil serine proteases (NSPs). Therefore, Cat C is an attractive target for treatment of inflammatory diseases mediated by NSPs overactivation. In previous study, compounds 54 and 77 were reported to be the first non-peptidyl non covalent Cat C inhibitors, with good enzyme inhibitory activity and NSPs activation inhibition, but their pharmacokinetic (PK) properties were unsatisfactory. In this study, starting from 77, after several rounds of structure-based design and modification, compound SF38, a novel Cat C inhibitor bearing a unique thiophene structure was identified, which exhibited strong inhibitory activity against Cat C (IC50 = 59.9 nM). Further mechanism study and in vivo evaluation showed that SF38 inhibited the Cat C activity in bone marrow and blood, decreased the activation of NSPs, and exhibited anti-inflammatory activity in an animal model of acute lung injury, with acceptable PK properties (F = 42.07%). These results enriched the structure-activity relationship (SAR) of Cat C inhibitor with thiophene structure characteristic, and proved the broad prospect of non-peptidyl non-covalent Cat C inhibitor. (C) 2022 Elsevier Masson SAS. All rights reserved.

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