- Pyrazole amide derivatives as well as preparation method and application thereof
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The invention relates to pyrazole derivatives represented by a general formula I shown in the description, or a stereoisomer and tautomer of the pyrazole derivatives, a preparation method of the pyrazole derivatives, and an application of the of the pyraz
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Paragraph 0140; 0147-0152
(2019/05/16)
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- Fragment-based lead generation of 5-phenyl-1H-pyrazole-3-carboxamide derivatives as leads for potent factor xia inhibitors
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FXIa is suggested as a major target for anticoagulant drug discovery because of reduced risk of bleeding. In this paper, we defined 5-phenyl-1H-pyrazole-3-carboxylic acid derivatives as privileged fragments for FXIa inhibitors' lead discovery. After repla
- Wei, Qunchao,Zheng, Zhichao,Zhang, Shijun,Zheng, Xuemin,Meng, Fancui,Yuan, Jing,Xu, Yongnan,Huang, Changjiang
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- Pyrazole derivatives as partial agonists for the nicotinic acid receptor
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Nicotinic acid as a hypolipidemic agent appears unique due to its potential to increase HDL cholesterol levels to a greater extent than other drugs. However, it has some side effects, among which severe skin flushing is the most frequent and often limits patients' compliance. In a search for novel agonists for the recently identified and cloned G protein-coupled nicotinic acid receptor, we synthesized a series of substituted pyrazole-3-carboxylic acids that proved to have substantial affinity for this receptor. The affinities were measured by inhibition of [3H] nicotinic acid binding to rat spleen membranes. Potencies and intrinsic activities relative to nicotinic acid were determined by their effects on [35S]GTPγS binding to rat adipocyte and spleen membranes. Interestingly, most compounds were partial agonists. In particular, 2-diazabicyclo-[3,3,O 4,8]octa-3,8-diene-3-carboxylic acid (4c) and 5-propylpyrazole-3-carboxylic acid (4f) proved active with Ki values of approximately 0.15 μM and EC50 values of approximately 6 μM, while their intrinsic activity was only ~50% when compared to nicotinic acid. Even slightly more active was 5-butylpyrazole-3-carboxylic acid (4g) with a Ki value of 0.072 μM, an EC50 value of 4.12 μM, and a relative intrinsic activity of 75%. Of the aralkyl derivatives, 4q (5-(3-chlorobenzyl)pyrazole-3-carboxylic acid) was the most active with a relatively low intrinsic activity of 39%. Partial agonism of the pyrazole derivatives was confirmed by inhibition of G protein activation in response to nicotinic acid by these compounds. The pyrazoles both inhibited the maximum effect elicited by 100 μM nicotinic acid and concentration dependently shifted nicotinic acid concentration-response curves to the right, pointing to a competive mechanism of action.
- Van Herk,Brussee,Van den Nieuwendijk,Van der Klein,IJzerman,Stannek,Burmeister,Lorenzen
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p. 3945 - 3951
(2007/10/03)
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