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• W3202040227 abstract "Targeting RIPK1 is a promising strategy for the treatment or alleviation of acute lung injury (ALI). SZM594, a benzothiazole compound previously developed by our research group, possessed good dual-targeting receptor-interacting protein kinase 1 (RIPK1) and RIPK3 activity and anti-necroptosis activity as well as acceptable in vivo efficacy. In this study, the cyclopropyl moiety of SZM594 was modified based on a structure-based design strategy. The resulting cyclohexanone-containing analogue 41 improved the selectivity toward RIPK1 over RIPK3 and the anti-necroptosis activity was also increased compared with those of SZM594. More importantly, compound 41 could inhibit the tumor necrosis factor-α (TNF-α) expression in lipopolysaccharide (LPS)-induced peritoneal macrophage cell model, and significantly alleviate LPS-induced ALI in a mouse model. This compound could significantly inhibit the expressions of the phosphorylation of RIPK1 and down-stream RIPK3 and mixed lineage kinase domain-like protein (MLKL). Thus, these cyclohexanone-containing benzothiazole analogues represent promising lead structures for the discovery of novel protective agents of ALI." @default.
• W3202040227 created "2021-10-11" @default.
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• W3202040227 date "2022-05-01" @default.
• W3202040227 modified "2023-10-17" @default.
• W3202040227 title "Structure-based optimizations of a necroptosis inhibitor (SZM594) as novel protective agents of acute lung injury" @default.
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• W3202040227 doi "https://doi.org/10.1016/j.cclet.2021.09.059" @default.
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