- Identification and Biological Evaluation of Novel Type II B-RafV600E Inhibitors
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The mitogen-activated protein kinase (MAPK) pathway plays a vital role in signal transduction networks. Severe diseases may be triggered if it is disturbed by mutated components, especially the kinase B-RafV600E. New inhibitors of the kinase ar
- Wang, Peng-Fei,Wang, Ze-Feng,Qiu, Han-Yue,Huang, Yue,Hu, Hui-Min,Wang, Zhong-Chang,Zhu, Hai-Liang
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Read Online
- Copper-Catalyzed N1 Coupling of 3-Aminoindazoles and Related Aminoazoles with Aryl Bromides
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The N1-selective arylation of 3-aminoindazoles using copper catalysis is herein reported. The reaction uses readily accessible aryl bromides as coupling partners, including those from heterocycles, and allows easy access to a broad variety of substituted 3-aminoindazoles. The methodology was also examined on other aminoazoles of interest for the pharmaceutical industry.
- Cyr, Patrick,Joseph-Valcin, Eve-Marline,Boissarie, Patrick,Simoneau, Bruno,Marinier, Anne
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supporting information
(2021/12/02)
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- Design and synthesis of anti-tumor compounds containing ferulic acid-pyrazole skeleton
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The invention discloses design and a preparation method of an anti-tumor compound containing a ferulic acid-pyrazole skeleton. The structure of the anti-tumor compound is shown as a formula in the specification.
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Paragraph 0024-0025; 0029; 0031-0032; 0035
(2021/04/28)
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- HSP90 INHIBITORS AND USES THEREOF
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Herein is described the design and synthesis of resorcylate aminopyrazole compounds. These compounds show broad, potent and fungal-selective Hsp90 inhibitory activity. These compounds also find use in treating Hsp90 related deseases.
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Paragraph 00517-00518; 00519-00521
(2020/11/23)
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- Cu-Catalyzed Couplings of Heteroaryl Primary Amines and (Hetero)aryl Bromides with 6-Hydroxypicolinamide Ligands
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A family of 6-hydroxypicolinamide ligands have been identified as effective supporting ligands for Cu-catalyzed couplings of heteroaryl bromides and chlorides with heteroaryl primary amines. The C-N couplings are carried out at 80-120 °C in DMSO or sulfolane using K2CO3 or K3PO4 as the base with 2-10 mol % CuI and supporting ligand. The strength of the base was found to have an impact on the chemoselectivity and rate. The use of K2CO3 as the base enabled selective C-N coupling of aryl bromides over aryl chlorides with 2-5 mol % Cu at 80-120 °C. With K3PO4 as the base, aryl chlorides are capable of undergoing C-N coupling, though 5-10 mol % Cu is required at 120-130 °C. Members of the ligand family are straightforward to prepare in one step from 6-hydroxypicolinic acid and the corresponding anilines.
- Bernhardson, David J.,Widlicka, Daniel W.,Singer, Robert A.
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p. 1538 - 1551
(2019/09/04)
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- IRAK4 INHIBITOR AND USE THEREOF
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The present invention relates to a compound inhibiting the activity of an IRAK4 kinase, a pharmaceutical composition thereof, a use thereof in preparing drugs, a method in which same is used for inhibiting the activity of the IRAK4 kinase and a method in which same is used for treating and/or preventing IRAK4 kinase mediated diseases or conditions in mammals (particularly humans). The compound has a structural formula I.
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Paragraph 0143; 0144
(2018/07/05)
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- Design of potent B-RafV600E inhibitors by multiple copy simulation search strategy
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B-Raf kinase is a vital intermedium in the mitogen-activated protein kinase (MAPK) signaling pathway, which transforms extracellular signals into cellular mechanisms. Mutations in this kinase, for instance, the most common V600E mutation, can lead to the ERK signaling pathologically activated and hence cause severe diseases such as somatic tumors. So far, the development of B-Raf inhibitors has made remarkable progress. However, the resistance and relapse of approved Raf drugs have been widely reported, and the optimization for old drugs and the discovery for new inhibitors still remain a significant task. In this study, we designed and evaluated a series of novel B-RafV600E inhibitors. A fragment library has been established before the docking simulation carried out using the MCSS strategy (multicopy simulation search). The appropriate fragments were reassembled to provide new candidate compounds, which were further screened by iterative docking simulations and molecular dynamics. Bioassays were carried out to evaluate the pharmacological profile of the compounds identified and synthesized. The result showed that compound 5n had an impressive enzyme inhibitory and antiproliferation activity, suggesting a promising potential in the future study.
- Wang, Ze-Feng,Wang, Peng-Fei,Ma, Jun-Ting,Chai, Ying-Zi,Hu, Hui-Min,Gao, Wen-Long,Wang, Zhong-Chang,Wang, Bao-Zhong,Zhu, Hai-Liang
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p. 567 - 574
(2017/12/26)
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- Design, synthesis, and biological evaluation of pyrazole derivatives containing acetamide bond as potential BRAFV600E inhibitors
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With the increasingly acquired resistance, relapse and side effects of known marketed BRAFV600E inhibitors, it's significant to design the more effective and novel drugs. In this study, a series of novel pyrazole derivatives containing acetamid
- Wang, Chen-Ru,Wang, Ze-Feng,Shi, Lu,Wang, Zhong-Chang,Zhu, Hai-Liang
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supporting information
p. 2382 - 2390
(2018/06/25)
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- Depsipeptides Featuring a Neutral P1 Are Potent Inhibitors of Kallikrein-Related Peptidase 6 with On-Target Cellular Activity
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Kallikrein-related peptidase 6 (KLK6) is a secreted serine protease that belongs to the family of tissue kallikreins (KLKs). Many KLKs are investigated as potential biomarkers for cancer as well as therapeutic drug targets for a number of pathologies. KLK6, in particular, has been implicated in neurodegenerative diseases and cancer, but target validation has been hampered by a lack of selective inhibitors. This work introduces a class of depsipeptidic KLK6 inhibitors, discovered via high-throughput screening, which were found to function as substrate mimics that transiently acylate the catalytic serine of KLK6. Detailed structure-activity relationship studies, aided by in silico modeling, uncovered strict structural requirements for potency, stability, and acyl-enzyme complex half-life. An optimized scaffold, DKFZ-251, demonstrated good selectivity for KLK6 compared to other KLKs, and on-target activity in a cellular assay. Moreover, DKFZ-633, an inhibitor-derived activity-based probe, could be used to pull down active endogenous KLK6.
- De Vita, Elena,Schüler, Peter,Lovell, Scott,Lohbeck, Jasmin,Kullmann, Sven,Rabinovich, Eitan,Sananes, Amiram,He?ling, Bernd,Hamon, Veronique,Papo, Niv,Hess, Jochen,Tate, Edward W.,Gunkel, Nikolas,Miller, Aubry K.
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supporting information
p. 8859 - 8874
(2018/10/09)
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- Design and synthesis of diphenyl urea derivative anti-tumor compounds containing pyrazol frameworks
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The invention discloses diphenyl urea derivatives containing pyrazol frameworks and a prepration method thereof. The structural formula of the diphenyl urea derivatives containing pyrazol frameworks is as shown in the specification, wherein R1 is selected
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Paragraph 0029
(2017/09/18)
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- 4,6 DIHYDROPYRROLO [3,4-C] PYRAZOLE-5 (1H)-CARBONITRILE DERIVATES FOR TRATING CANCER
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The present invention relates to novel compounds and methods for the manufacture of inhibitors of deubiquitylating enzymes (DUBs) and/ or desumoylating enzymes. In particular, the invention relates to the inhibition of ubiquitin C-terminal hydrolase 7 or
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Page/Page column 44
(2017/10/13)
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- Copper-catalyzed, oxidative sp2 C-H cyanation: Facile synthesis of aromatic carbonitriles
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Cu(OAc)2-catalyzed regioselective oxidative C-H cyanation of two different types of aromatics was described, providing facile access to functionalized heterocycles in good yields. Control experiments suggest the copper chelation-assisted oxidative C-H activation mechanism. ARKAT-USA, Inc.
- Liu, Jin-Qiang,Hao, Bao-Yu,Zou, Hao,Zhang, Wei-Han,Chen, Xin-Zhi
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- PYRIMIDINE INHIBITORS OF KINASES
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The present invention relates to compounds of formula (I) or pharmaceutical acceptable salts, wherein A1, A2, A3, A4, X and Y are defined in the description. The present invention relates also to methods of making said compounds, and compositions containing said compounds which are useful for inhibiting kinases such as aurora and KDR.
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- NOVEL PIPERAZINE DERIVATIVES AS INHIBITORS OF STEAROYL-CoA DESATURASE
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The present invention relates to piperazine derivatives that act as inhibitors of stearoyl-CoA desaturase. The invention also relates to methods of preparing the compounds, compositions containing the compounds, and to methods of treatment using the compounds.
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Page/Page column 39; 40
(2009/10/01)
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