822-85-5Relevant articles and documents
Quinoxaline compound, preparation method and application of quinoxaline compound in medicine
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Paragraph 0203-0206, (2021/07/24)
The invention provides a quinoxaline compound, a preparation method and application of the quinoxaline compound in medicine, and particularly relates to a quinoxaline compound with PAR4 antagonistic activity, a preparation method of the quinoxaline compound, a pharmaceutical composition containing the quinoxaline compound and application of the quinoxaline compound. Specifically, the invention provides a compound shown as a general formula I and/or II or a tautomer or pharmaceutically acceptable salt thereof, a preparation method of the compound, and application of the compound or the tautomer or the pharmaceutically acceptable salt in medicines for preventing and/or treating thromboembolic diseases.
Copper-Mediated Dichotomic Borylation of Alkyne Carbonates: Stereoselective Access to (E)-1,2-Diborylated 1,3-Dienes versus Traceless Monoborylation Affording α-Hydroxyallenes
Guo, Kun,Kleij, Arjan W.
supporting information, p. 4901 - 4906 (2021/01/21)
A mild copper-mediated protocol has been developed for borylation of alkynyl cyclic carbonates. Depending on the nature of the borylating reaction partner, either stereoselective diborylation of the propargylic surrogate takes place, providing convenient access to (E)-1,2-borylated 1,3-dienes, or traceless monoborylation occurs, which leads to α-hydroxyallenes as the principal product. The dichotomy in this borylation protocol has been scrutinized by several control experiments, illustrating that a relatively small change in the diboron(4) reagent allows for competitive alcohol-assisted protodemetalation to forge an α-hydroxyallene product under ambient conditions.
Synthesis and evaluation of novel and potent protease activated receptor 4 (PAR4) antagonists based on a quinazolin-4(3H)-one scaffold
Kong, Yi,Li, Shanshan,Liu, Shangde,Xie, Roujie,Yuan, Duo,Zhu, Xiong
supporting information, (2021/08/16)
Protease activated receptor 4 (PAR4) is an important target in antiplatelet therapy to reduce the risk of heart attack and thrombotic complications in stroke. PAR4 antagonists can prevent harmful and stable thrombus growth, while retaining initial thrombus formation, by acting on the late diffusion stage of platelet aggregation, and may provide a safer alternative to other antiplatelet agents. To date, only two PAR4 antagonists, BMS-986120 and BMS-986141 have entered clinical trials for thrombosis. Thus, the development of a potent and selective PAR4 antagonist with a novel chemotype is highly desirable. In this study, we explored the activity of quinazolin-4(3H)-one-based PAR4 antagonists, beginning with their IDT analogues. By repeated structural optimisation, we developed a series of highly selective PAR4 antagonists with nanomolar potency on human platelets. Of these, 13 and 30g, with an 8-benzo[d]thiazol-2-yl-substituted quinazolin-4(3H)-one structure, showed optimal activity (h. PAR4-AP PRP IC50 = 19.6 nM and 6.59 nM, respectively) on human platelets. Furthermore, 13 and 30g showed excellent selectivity for PAR4 versus PAR1 and other receptors (IC50s > 10 μM) on human platelets. And 13 and 30g were lack of cross-reactivity for PAR1 or PAR2 (PAR1 AP FLIPR IC50 > 3162 nM, PAR2 AP FLIPR IC50 > 1000 nM) in the calcium mobilization assays. Metabolic stability assays and cytotoxicity tests of 13 and 30g indicated that these compounds could sever as promising drug candidates for the development of novel PAR4 antagonists. In summary, the quinazolin-4(3H)-one-based analogues are the first reported chemotypes with excellent activity and selectivity against PAR4, and, in the current study, we expanded the structural diversity of PAR4 antagonists. The two compounds, 13 and 30g, found in our study could be promising starting points with great potential for further research in antiplatelet therapy.
