- Piperidine compound and preparation method and medical application thereof
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The invention discloses a piperidine compound shown as a formula (I) and a preparation method and medical application thereof, and particularly relates to a piperidine USP7 inhibitor compound or pharmaceutically acceptable salt or ester or solvate thereof and a preparation method and application of the piperidine USP7 inhibitor compound or pharmaceutically acceptable salt or ester or solvate thereof. The compound provided by the invention can inhibit the activity of USP7 enzyme, has very good selectivity and druggability, and can be used for preparing medicines for preventing or treating tumor diseases or virus infectious diseases.
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- N-benzylpiperidinol derivatives as novel USP7 inhibitors: Structure–activity relationships and X-ray crystallographic studies
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USP7 as a deubiquitinase plays important roles in regulating the stability of some oncoproteins including MDM2 and DNMT1, and thus represents a potential anticancer target. Through comparative analysis of USP7 co-crystal structures in complex with the rep
- Chen, Caiping,Chen, Hui,Cheng, Keguang,Li, Minglei,Liu, Jun,Liu, Shengjie,Sun, Hongbin,Wang, Yue,Wen, Xiaoan,Xu, Qing-Long,Yuan, Haoliang,Zhou, Jin,Zhou, Shuxi,Zhou, Xinyu
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- New pyrazolopyrimidine derivatives as Leishmania amazonensis arginase inhibitors
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Arginase performs the first enzymatic step in polyamine biosynthesis in Leishmania and represents a promising target for drug development. Polyamines in Leishmania are involved in trypanothione synthesis, which neutralize the oxidative burst of reactive oxygen species (ROS) and nitric oxide (NO) that are produced by host macrophages to kill the parasite. In an attempt to synthesize arginase inhibitors, six 1-phenyl-1H-pyrazolo[3,4-d]pyrimidine derivatives with different substituents at the 4-position of the phenyl group were synthesized. All compounds were initially tested at 100 μM concentration against Leishmania amazonensis ARG (LaARG), showing inhibitory activity ranging from 36 to 74%. Two compounds, 1 (R=H) and 6 (R=CF3), showed arginase inhibition >70% and IC50 values of 12 μM and 47 μM, respectively. Thus, the kinetics of LaARG inhibition were analyzed for compounds 1 and 6 and revealed that these compounds inhibit the enzyme by an uncompetitive mechanism, showing Kis values, and dissociation constants for ternary complex enzyme-substrate-inhibitor, of 8.5 ± 0.9 μM and 29 ± 5 μM, respectively. Additionally, the molecular docking studies proposed that these two uncompetitive inhibitors interact with different LaARG binding sites, where compound 1 forms more H-bond interactions with the enzyme than compound 6. These compounds showed low activity against L. amazonensis free amastigotes obtained from mice lesions when assayed with as much as 30 μM. The maximum growth inhibition reached was between 20 and 30% after 48 h of incubation. These results suggest that this system can be promising for the design of potential antileishmanial compounds.
- Feitosa, Livia M.,da Silva, Edson R.,Hoelz, Lucas V.B.,Souza, Danielle L.,Come, Julio A.A.S.S.,Cardoso-Santos, Camila,Batista, Marcos M.,Soeiro, Maria de Nazare C.,Boechat,Pinheiro, Luiz C.S.
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p. 3061 - 3069
(2019/06/08)
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- Synthesis and anti-Plasmodium falciparum evaluation of novel pyrazolopyrimidine derivatives
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Nine 1-phenyl-1H-pyrazolo[3,4-d]pyrimidine derivatives with different substituents in the 4-position of the phenyl group and benzenesulfonamide moiety were synthesized and evaluated against Plasmodium falciparum. Six compounds exhibited activity in vitro against the chloroquine-resistant clone W2 with IC50 values ranging from 5.13 to 12.22 μM. The most active derivative with substituents R1 = F / R2 = CH3 exhibited an IC50 value of 5.13 μM and an IS value of 62.90, which was higher than that of the control drug sulfadoxine. For this reason, it is possible to conclude that the 1H-pyrazolo[3,4-d]pyrimidine system is promising as a prototype for further studies of antimalarial candidates.
- Silveira, Flávia F.,Feitosa, Lívia M.,Mafra, Jo?o C. M.,Ferreira, Maria de Lourdes G.,Rogerio, Kamilla R.,Carvalho, Leonardo J. M.,Boechat, Nubia,Pinheiro, Luiz C. S.
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p. 1876 - 1884
(2018/06/25)
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- Identification of novel GLUT inhibitors
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The compound class of 1H-pyrazolo[3,4-d]pyrimidines was identified using HTS as very potent inhibitors of facilitated glucose transporter 1 (GLUT1). Extensive structure–activity relationship studies (SAR) of each ring system of the molecular framework was established revealing essential structural motives (i.e., ortho-methoxy substituted benzene, piperazine and pyrimidine). The selectivity against GLUT2 was excellent and initial in vitro and in vivo pharmacokinetic (PK) studies are encouraging.
- Siebeneicher, Holger,Bauser, Marcus,Buchmann, Bernd,Heisler, Iring,Müller, Thomas,Neuhaus, Roland,Rehwinkel, Hartmut,Telser, Joachim,Zorn, Ludwig
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p. 1732 - 1737
(2016/07/27)
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- PYRROLO AND PYRAZOLOPYRIMIDINES AS UBIQUITIN-SPECIFIC PROTEASE 7 INHIBITORS
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The invention relates to inhibitors of USP7 inhibitors useful in the treatment of cancers, neurodegenerative diseases, immunological disorders, inflammatory disorders, cardiovascular diseases, ischemic diseases, viral infections and diseases, and bacterial infections and diseases, having the Formula: where m, n, X1, X2, R1-R5, R5′ and R6 are described herein.
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- Microwave-assisted protocols for the expedited synthesis of pyrazolo[1,5-a] and [3,4-d]pyrimidines
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General, high-yielding MAOS protocols for the expedited synthesis of functionalized pyrazolo[1,5-a]pyrimidines and pyrazolo[3,4-b]pyrimidines, as well as their pyrazole precursors, are described amenable to an iterative analogue library synthesis strategy for lead optimization.
- Daniels, R. Nathan,Kim, Kwangho,Lebois, Evan P.,Muchalski, Hubert,Hughes, Mary,Lindsley, Craig W.
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p. 305 - 310
(2008/09/17)
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