- Discovery of pyrazole derivatives as cellular active inhibitors of histone lysine specific demethylase 5B (KDM5B/JARID1B)
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KDM5B (also known as PLU-1 and JARID1B) is 2-oxoglutarate and Fe2+ dependent oxygenase that acts as a histone H3K4 demethylase, which is a key participant in inhibiting the expression of tumor suppressors as a drug target. Here, we present the discovery of pyrazole derivatives compound 5 by structure-based virtual screening and biochemical screening with IC50 of 9.320 μM against KDM5B, and its subsequent optimization to give 1-(4-methoxyphenyl)-N-(2-methyl-2-morpholinopropyl)-3-phenyl-1H-pyrazole-4-carboxamide (27 ab), a potent KDM5B inhibitor with IC50 of 0.0244 μM. In MKN45 cells, compound 27 ab can bind and stabilize KDM5B and induce the accumulation of H3K4me2/3, bona fide substrates of KDM5B, while keep the amount of H3K4me1, H3K9me2/3 and H3K27me2 without change. Further biological study also indicated that compound 27 ab is a potent cellular active KDM5B inhibitor that can inhibit MKN45 cell proliferation, wound healing and migration. In sum, our finding gives a novel structure for the discovery of KDM5B inhibitor and targeting KDM5B may be a new therapeutic strategy for gastric cancer treatment.
- Liang, Qianqian,Liu, Hong-Min,Ma, Li-Ying,Ren, Hongmei,Wu, Yang,Zhang, Kun,Zhang, Xinhui,Zhao, Bing,Zheng, Yi-Chao
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- Discovery and optimization of pyrazole amides as antagonists of CCR1
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A HTS screen for CCR1 antagonists afforded a novel sub-micromolar hit 5 containing a pyrazole core. In this report the design, optimization, and SAR of novel CCR1 antagonists based on a pyrazole core motif is presented. Optimization led to the advanced ca
- Harcken, Christian,Sarko, Christopher,Mao, Can,Lord, John,Raudenbush, Brian,Razavi, Hossein,Liu, Pingrong,Swinamer, Alan,Disalvo, Darren,Lee, Thomas,Lin, Siqi,Kukulka, Alison,Grbic, Heather,Patel, Mita,Patel, Monica,Fletcher, Kim,Joseph, David,White, Della,Amodeo, Laura,Berg, Karen,Brown, Maryanne,Thomson, David S.
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p. 435 - 440
(2018/11/23)
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- PYRAZOLE COMPOUNDS AS CCR1 ANTAGONISTS
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Disclosed are compounds of the formula I which block the interaction of CCR1 and its ligands and are thus useful for treating a variety of diseases and disorders that are mediated or sustained through the activity of CCR1 including autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis. Also disclosed are pharmaceutical compositions comprising these compounds, methods of using these compounds in the treatment of various diseases and disorders, processes for preparing these compounds and intermediates useful in these processes.
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Page/Page column 51
(2010/01/29)
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- INHIBITORS OF CHECKPOINT KINASES
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The instant invention provides for compounds which comprise fused pyrazoles that inhibit CHK1 activity. The invention also provides for compositions comprising such inhibitory compounds and methods of inhibiting CHK1 activity by administering the compound
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- AMIDE COMPOUNDS AND MEDICINAL USE THEREOF
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The present invention relates to a compound of the formula wherein R1 is substituted aryl, heteroaryl and the like, R2 and R3 are hydrogen, alkyl, halogen, hydroxyl group and the like, Q is N, CH and the like, W is hydrogen, alkyl, hydroxycarbonylalkyl and the like, X is halogen, cyano, nitro, amino and the like, X' is hydrogen, halogen, cyano, nitro, and Y is alkyl, hydroxyl group, alkoxy, mercapto and the like and a salt thereof, and a medicine containing the said compound. The compound of the present invention shows a superior inhibitory effect on activated lymphocytes proliferation and is useful as an agent for the prophylaxis or treatment of various autoimmune diseases.
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- CONVERSION DE L'ACETYL-5 URACILE EN DERIVES PYRAZOLIQUES PAR L'HYDRAZINE ET LES HYDRAZINES MONOSUBSTITUEES
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5-Acetyl uracile 1 is easily transformed by hydrazine and methylhydrazine into 4-allophanoyl-3-methyl pyrazole 2 (R=H) and 4-allophanoyl-1,3-dimethyl pyrazole 2 (R=CH3).The pyrazoles 2, in boiling butanol and in the presence of hydrochloric acid lead resp
- Bajnati, Abdelilah,Hubert-Habart, Michel
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p. 540 - 547
(2007/10/02)
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