29056-03-9Relevant articles and documents
Discovery of a novel and potent inhibitor with differential species-specific effects against NLRP3 and AIM2 inflammasome-dependent pyroptosis
Bin, Huachao,Cao, Zhixing,Chen, Pei,Jiao, Yan,Li, Linli,Lin, Guifeng,Lin, Wanting,Mu, Bo,Nan, Jinshan,Pan, Shulei,Pan, Zhiling,Wang, Falu,Xia, Anjie,Yang, Shengyong,Yang, Shunhua,Zhang, Shanshan,Zhang, Yun,Zhou, Nenghua
, (2022/02/21)
The NLRP3 inflammasome, which regulated a proinflammatory programmed cell death form termed pyroptosis, is involved in the pathological process of various human diseases, such as multiple sclerosis, type 2 diabetes, and gout. Thus, compounds inhibiting activation of the NLRP3 inflammasome can be promising treatments for these diseases. In this study, we conducted a phenotypic screening against NLRP3-dependent pyroptosis and discovered the hit compound 1, which showed moderate antipyroptotic activity. Chemistry efforts to improve potency of 1 resulted in a novel compound 59 (J114), which exhibited a half-maximal inhibitory concentration (IC50) of 0.077 ± 0.008 μM against cell pyroptosis. Interestingly, unlike all pyroptosis inhibitors currently reported, the activity of J114 showed significant differences in human- and mouse-derived cells. The IC50 of J114-mediated inhibition of IL-1β secretion by human THP-1 macrophages was 0.098 μM, which was nearly 150-fold and 500-fold more potent than that of J774A.1 (14.62 μM) and bone marrow-derived macrophages (BMDMs) (48.98 μM), respectively. Further studies showed that J114 displayed remarkable inhibitory activity against NLRP3- and AIM2-but not NLRC4-dependent activation of caspase-1 and the release of IL-1β in human THP-1 macrophages. Mechanistically, J114 disturbed the interaction of NLRP3 or AIM2 with the adaptor protein ASC and inhibited ASC oligomerization. Overall, our study identified a unique molecule that inhibits NLRP3 and AIM2 inflammasome activation and has species differences, which is worthy of further research to understand the differential regulation of the NLRP3 and AIM2 inflammasomes in humans and mice.
C1 substituted 3, 4 - ISO-quinoline alkaloids of the preparation and its medicinal use
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Paragraph 0066; 0072; 0073, (2019/03/28)
The invention belongs to the field of medical technology. The invention relates to a structure of the formula (I) indicated by the C1 substituted 3, 4 - ISO alkaloid or its pharmaceutically acceptable salt preparation method and medical use thereof. The invention to BOC - L - phenylalanine as raw materials, with 3, 4 - dimethoxyphenethylamine to N - acylated condensation and then remove the BOC group gets the (S)- 2 - amino - N - (3, 4 - dimethyl practiced with ethyl) - 3 - benzyl amide intermediate 1, intermediate 1 or phenethylamine derivatives with the prepared containing different substituent phenyllacetyl carries out amidation reaction, finally loop Bischler - Napieralski reaction. After activeness screening tests, the compounds of this invention possess pancrelipase inhibition, in the development into a lipase inhibitor and for preventing or treating hyperlipidemia, diabetes, obesity or metabolic syndrome and other diseases has a good application prospect.
9 - Substituted derivative of berberine at the preparation and its use in medicine (by machine translation)
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Paragraph 0034; 0038; 0039, (2018/04/03)
The invention belongs to the field of medical technology. The invention relates to a structure of the formula (I) and formula (II) shown by the 9 bit - substituted berberine derivatives and their pharmaceutically acceptable salts thereof and its medical use. After activeness screening tests, the compounds of this invention possess pancrelipase inhibition, develop into the prospect of lipase inhibitors; in addition, the compounds of this invention fat-soluble than berberine increased, so that the development into the prevention or treatment of hyperlipidemia, diabetes, obesity or metabolic syndrome and other diseases in more application prospect. (by machine translation)
