Investigation on the chemical space of the substituted triazole thio-benzoxazepinone RIPK1 inhibitors

Hao, Yong; Shao, Hongming; Qu, Zhuo; Li, Jiao; Shi, Ying; Zhang, Wannian; Fu, Peng; Zhuang, Chunlin

doi:10.1016/j.ejmech.2022.114345

Cited by 11 publications

(18 citation statements)

References 32 publications

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“…SZM679 showed consistently high RIPK1 inhibitory activity with a K d of 8.6 nM, which was much higher than that of GSK'772 (K d = 31 nM). 32 SZM681 with a cyclohexanone ring showed the best RIPK1 inhibitory activity (K d = 4.5 nM) in this series. In the predicted binding mode of SZM679 with RIPK1, we can clearly observe that the fluoro group makes the phenylether bond to be in close proximity to the "DLG" gatekeeper of RIPK1.…”

Section: ■ Resultsmentioning

confidence: 99%

“…The binding activity toward RIPK3 was not demonstrated at 5000 nM. SZM679 showed consistently high RIPK1 inhibitory activity with a K d of 8.6 nM, which was much higher than that of GSK’772 ( K d = 31 nM) …”

Section: Resultsmentioning

confidence: 99%

“…Our data have clearly indicated that the selective inhibition of RIPK1 may account for decreasing inflammatory cytokines (IL-1β and IL-6) in AD brains. These findings are consistent with previous reports suggesting that RIPK1 is involved in different inflammatory diseases. ,, …”

Section: Discussionmentioning

confidence: 99%

“…These findings are consistent with previous reports suggesting that RIPK1 is involved in different inflammatory diseases. 28,29,32 Journal of Medicinal Chemistry In this study, only one dose was used to clarify the ameliorate effect of SZM679 in the cognitive dysfunction of mice. Furthermore, in vivo dose-dependent response would be carried out to understand the effect of the compound comprehensively, and more experiments should be performed for demonstrating the pharmacokinetics of SZM679 in mice including the concentration of SZM679 in brain.…”

Section: Szm679 Treatment Decreases the Expression Levels Of Inflamma...mentioning

confidence: 99%

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Discovery of a Trifluoromethoxy Cyclopentanone Benzothiazole Receptor-Interacting Protein Kinase 1 Inhibitor as the Treatment for Alzheimer’s Disease

Sun

Shao

et al. 2022

J. Med. Chem.

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Receptor-interacting protein kinase 1 (RIPK1) contributes to a broad set of inflammations and necroptosis in human diseases, which also plays an important role in the pathogenesis of Alzheimer’s disease (AD). The inhibition of RIPK1 could be a novel strategy to improve cognitive function. SZM679, a highly specific RIPK1 inhibitor (K d,RIPK1 = 8.6 nM, K d,RIPK3 > 5000 nM), was developed by our group with superior high antinecroptotic activity (EC50 = 2 nM), and investigated to completely reverse the tumor necrosis factor-induced systemic inflammatory response syndrome. In a streptozocin-induced AD-like mouse model, behavioral tests showed that SZM679 apparently ameliorated learning and memory dysfunction. Nissl staining revealed that SZM679 improved neuronal loss. Moreover, the Tau hyperphosphorylation, neuroinflammation, and the RIPK1 phosphorylation level in the hippocampus and cortex were significantly decreased in the SZM679-treated group. Collectively, SZM679 represents a promising lead structure for the discovery of novel RIPK1 inhibitory anti-AD agents.

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Section: ■ Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Szm679 Treatment Decreases the Expression Levels Of Inflamma...mentioning

confidence: 99%

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Discovery of a Trifluoromethoxy Cyclopentanone Benzothiazole Receptor-Interacting Protein Kinase 1 Inhibitor as the Treatment for Alzheimer’s Disease

Sun

Shao

et al. 2022

J. Med. Chem.

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“…The key intermediates m1 and m5 were generated following our previous report. 41 The intermediate m1 with various alkynylcontaining compounds underwent Sonogashira coupling to obtain m2. Treatment of m2 with Lawesson's reagent afforded the thio-benzoxazepinones m3, and then m4 was obtained by a de-protection using the CF 3 COOH or HCl.…”

Section: Resultsmentioning

confidence: 99%

Structure-Based Design of Novel Alkynyl Thio-Benzoxazepinone Receptor-Interacting Protein Kinase-1 Inhibitors: Extending the Chemical Space from the Allosteric to ATP Binding Pockets

et al. 2023

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Systemic inflammatory response syndrome (SIRS), characterized by severe systemic inflammation, represents a major cause of health loss, potentially leading to multiple organ failure, shock, and death. Exploring potent RIPK1 inhibitors is an effective therapeutic strategy for SIRS. Recently, we described thio-benzoxazepinones as novel RIPK1 inhibitors and confirmed their anti-inflammatory activity. Herein, we further synthesized novel thio-benzoxazepinones by introducing substitutions on the benzene ring by an alkynyl bridge in order to extend the chemical space from the RIPK1 allosteric to ATP binding pockets. The in vitro cell and kinase assays found that compounds 2 and 29 showed highly potent activity against necroptosis (EC50 = 3.7 and 3.2 nM) and high RIPK1 inhibitory activity (K d = 9.7 and 70 nM). Prominently, these two analogues possessed better in vivo anti-inflammatory effects than the clinical candidate GSK′772 and effectively blocked hypothermia and deaths in a TNFα-induced SIRS model.

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Profiling of the chemical space on the phenyl group of substituted benzothiazole RIPK3 inhibitors

Liang

Zhang

et al. 2023

Bioorganic Chemistry

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Investigation on the chemical space of the substituted triazole thio-benzoxazepinone RIPK1 inhibitors

Cited by 11 publications

References 32 publications

Discovery of a Trifluoromethoxy Cyclopentanone Benzothiazole Receptor-Interacting Protein Kinase 1 Inhibitor as the Treatment for Alzheimer’s Disease

Discovery of a Trifluoromethoxy Cyclopentanone Benzothiazole Receptor-Interacting Protein Kinase 1 Inhibitor as the Treatment for Alzheimer’s Disease

Structure-Based Design of Novel Alkynyl Thio-Benzoxazepinone Receptor-Interacting Protein Kinase-1 Inhibitors: Extending the Chemical Space from the Allosteric to ATP Binding Pockets

Profiling of the chemical space on the phenyl group of substituted benzothiazole RIPK3 inhibitors

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