- EIF4E INHIBITORS AND USES THEREOF
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The present invention provides compounds inhibiting elF4E activity, and compositions and methods of using thereof. Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful for treating a variety of diseases, dis
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Paragraph 00303
(2020/03/29)
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- Toward a treatment of diabesity: In vitro and in vivo evaluation of uncharged bromophenol derivatives as a new series of PTP1B inhibitors
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Protein tyrosine phosphatase 1B (PTP1B) has been considered as a validated biological target for type 2 diabetes treatment, but past endeavors to develop inhibitors of PTP1B into drugs have been unsuccessful. Two challenging aspects are selective inhibition and cell permeability. A structure-based strategy was employed to develop uncharged bromophenols as a new series of PTP1B inhibitors. The most potent compound 22 (LXQ46) inhibited PTP1B with an IC50 value of 0.190 μM, and showed remarkable selectivity over other protein tyrosine phosphatases (PTPs, 20–200 folds). In the SPR study, increasing concentrations of compound 22 led to concentration-dependent increases in binding responses, indicating that compound 22 could bind to the surface of PTP1B via noncovalent means. By treating insulin-resistant C2C12 myotubes with compound 22, enhanced insulin and leptin signaling pathways were observed. Long-term oral administration of compound 22 reduced the blood glucose level of diabetic BKS db mice. The glucose tolerance tests (OGTT) and insulin tolerance tests (ITT) in BKS db mice showed that oral administration of compound 22 could increase insulin sensitivity. In addition, long-term oral administration of compound 22 could protect mice from obesity, which was not the result of toxicity. Our pharmacokinetics results from the rat-based assays showed that orally administered compound 22 was absorbed rapidly from the gastrointestinal tract, extensively distributed to the tissues, and rapidly eliminated from the body. All these results indicate that compound 22 could serve as a qualified agent to treat type II diabetes.
- Li, Xiangqian,Xu, Qi,Li, Chao,Luo, Jiao,Li, Xiuxue,Wang, Lijun,Jiang, Bo,Shi, Dayong
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supporting information
p. 178 - 185
(2019/02/05)
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- SUBSTITUTED AMINOTHIAZOLES AS INHIBITORS OF NUCLEASES
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The invention provides compounds represented by the structural formula (1): wherein R1, R2, R3, R4, R5, R6 are as defined in the claims. The compounds are inhibitors of nucleases, and are useful in particular in a method of treatment and/or prevention of proliferative diseases, neurodegenerative diseases, and other genomic instability associated diseases.
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Page/Page column 14-15; 18; 46
(2019/11/12)
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- Design, synthesis and biological evaluation of uncharged catechol derivatives as selective inhibitors of PTP1B
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Protein tyrosine phosphatases 1B (PTP1B) is a promising and validated therapeutic target to effectively treat T2DM and obesity. However, the development of charged PTP1B inhibitors was restricted due to their low cell permeability and poor bioavailability. Based on active natural products, two series of uncharged catechol derivatives were identified as PTP1B inhibitors by targeting a secondary aryl phosphate-binding site as well as the catalytic site. The most potent inhibitor 22 showed an IC50 of 0.487?μM against PTP1B and strong selectivity (27-fold) over TCPTP. Kinetic studies were also performed that 22 act as a competitive PTP1B inhibitor. The treatment of C2C12 myotubes with 22 markedly increased the phosphorylation levels of IRβ, Akt and IRS1 phosphorylation. The similarity of its action profiling with that produced by insulin suggested its potential as a new non-insulin-dependent drug candidate.
- Li, Xiang-Qian,Xu, Qi,Luo, Jiao,Wang, Li-Jun,Jiang, Bo,Zhang, Ren-Shuai,Shi, Da-Yong
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p. 348 - 359
(2017/05/17)
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- Bromophenol-oxazole compound and its use in drug for treatment on diabetes mellitus type 2
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The invention relates to a chemical total synthesis method of novel bromophenol-oxazole PTP1B and its use in a drug for treatment on diabetes mellitus type 2. The PTP1B inhibitor has a structural formula shown in the description. The compound improves insulin receptor sensibility through inhibiting the activity of protein tyrosine phosphatase 1B and has good treatment effects on insulin resistance-type diabetes mellitus type 2.
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Paragraph 0026; 0027; 0029
(2017/08/19)
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- COMPOSITION FOR MAINTAINING PLATELET FUNCTION
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Provided is a composition for maintaining a function of platelets, having as an active ingredient a pyridone derivative represented by the following general formula (I), or a salt thereof (in the formula, ring A, R1, R2, R3/sup
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Paragraph 0212
(2016/07/05)
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- PYRIDONE DERIVATIVE AND MEDICINE CONTAINING SAME
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General formula (I): The present invention pertains to: a pyridone derivate or a salt thereof represented by general formula (I); or a medicine containing the pyridone derivative or salt thereof as an active ingredient. [In the formula, ring A, R1/s
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Paragraph 0122-0123
(2014/10/28)
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- Structural design, synthesis and structure-activity relationships of thiazolidinones with enhanced anti-Trypanosoma cruzi activity
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Pharmacological treatment of Chagas disease is based on benznidazole, which displays poor efficacy when administered during the chronic phase of infection. Therefore, the development of new therapeutic options is needed. This study reports on the structural design and synthesis of a new class of anti-Trypanosoma cruzi thiazolidinones (4 a-p). (2-[2-Phenoxy-1-(4-bromophenyl) ethylidene)hydrazono]-5-ethylthiazolidin-4-one (4 h) and (2-[2-phenoxy-1-(4- phenylphenyl)ethylidene)hydrazono]-5-ethylthiazolidin-4-one (4 l) were the most potent compounds, resulting in reduced epimastigote proliferation and were toxic for trypomastigotes at concentrations below 10 μM, while they did not display host cell toxicity up to 200 μM. Thiazolidinone 4 h was able to reduce the in vitro parasite burden and the blood parasitemia in mice with similar potency to benznidazole. More importantly, T. cruzi infection reduction was achieved without exhibiting mouse toxicity. Regarding the molecular mechanism of action, these thiazolidinones did not inhibit cruzain activity, which is the major trypanosomal protease. However, investigating the cellular mechanism of action, thiazolidinones altered Golgi complex and endoplasmic reticulum (ER) morphology, produced atypical cytosolic vacuoles, as well as induced necrotic parasite death. This structural design employed for the new anti-T. cruzi thiazolidinones (4 a-p) led to the identification of compounds with enhanced potency and selectivity compared to first-generation thiazolidinones. These compounds did not inhibit cruzain activity, but exhibited strong antiparasitic activity by acting as parasiticidal agents and inducing a necrotic parasite cell death. Stop the cycle! The attachment of an aryl ring to the iminic carbon produced thiazolidinones that are conformationally more restricted than first-generation thiazolidinones. This enhanced the potency of antiparasitic thiazolidinones, as observed under treatment with compound 4 h where parasite development and invasion in host cells were substantially reduced. Copyright
- Moreira, Diogo Rodrigo Magalhaes,Lima Leite, Ana Cristina,Cardoso, Marcos Verissimo Oliveira,Srivastava, Rajendra Mohan,Hernandes, Marcelo Zaldini,Rabello, Marcelo Montenegro,Da Cruz, Luana Faria,Ferreira, Rafaela Salgado,De Simone, Carlos Alberto,Meira, Cassio Santana,Guimaraes, Elisalva Teixeira,Da Silva, Aline Caroline,Dos Santos, Thiago Andre Ramos,Pereira, Valeria Rego Alves,Pereira Soares, Milena Botelho
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supporting information
p. 177 - 188
(2014/01/17)
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- A newly synthesized thiazole derivative as a fluoride ion chemosensor: Naked-eye, spectroscopic, electrochemical and NMR studies
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2,3-Indoledione 3-thiosemicarbazone (TSCI) and a novel compound 3-(2-(4-(4-phenoxyphenyl)thiazol-2-yl)hydrazono)indolin-2-one (FTHI) were synthesized with high yield and characterized by spectroscopic techniques. The complexation behaviors of TSCI and FTHI for various anionic species (F -, Cl-, Br-, I-, NO2-, NO3-, BzO-, HSO4-, ClO4-) in CH3CN were investigated and compared by UV-vis spectroscopy, cyclic voltammetry and 1H NMR titration techniques. FTHI showed high degree of selectivity for fluoride over other anions. This selectivity could be easily observed by the naked eye, indicating that FTHI is potential colorimetric sensor for fluoride anion.
- Sarigüney, Ahmet Burak,Saf, Ahmet ?zgür,Co?kun, Ahmet
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p. 575 - 582
(2014/04/17)
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- Synthesis of novel benzo-fused heteroaryl derivatives as Ca 2+/calmodulin-dependent protein kinase II inhibitors
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Based on the structure activity relationship of 2-(4-phenoxybenzoyl)-5- hydroxyindole (1), a novel structural class of Ca2+ /calmodulin-dependent protein kinase II (CaMKII) inhibitors were synthesized. We show in this study that the acidic prot
- Komiya, Masafumi,Asano, Shigehiro,Koike, Nobuyuki,Koga, Erina,Igarashi, Junetsu,Nakatani, Shogo,Isobe, Yoshiaki
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p. 1094 - 1097
(2013/11/19)
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- Design, synthesis and docking-based 3D-QSAR study of novel 2-substituted 2-aminopropane-1,3-diols as potent and selective agonists of sphingosine-1-phosphate 1 (S1P1) receptor
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Spingosine-1-phosphate receptor 1 (S1P1) has been actively pursued as an important therapeutic target in immune regulation. A series of 2-substituted 2-aminopropane-1,3-diols were designed and synthesized as selective S1P1 agonists. Most of the compounds with a biphenyl ether scaffold showed moderate to excellent S1P1/S1P3 selectivity. Compound 40c is identified as a potent S1P1 agonist with 350-fold S1P1/S1P3 selectivity. 39c, the alcohol form of 40c exerted good lymphopenia activity in vivo but with weak influence on heart rate. To investigate the SARs of 2-substituted 2-aminopropane-1,3-diols in more details, COMFA (q2 = 0.547, r2 = 0.986) and COMSIA (q 2 = 0.544, r2 = 0.943) models were established based on molecular docking alignment, which were validated with high reliability in predicting activities of agonists. The 3D-QSAR models will be helpful in the design of novel, potent and selective S1P1 agonists. The Royal Society of Chemistry.
- Tian, Yulin,Jin, Jing,Wang, Xiaojian,Han, Weijuan,Li, Gang,Zhou, Wanqi,Xiao, Qiong,Qi, Jianguo,Chen, Xiaoguang,Yin, Dali
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supporting information
p. 1267 - 1274
(2013/09/12)
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- ALKALOID AMINOESTER DERIVATIVES AND MEDICINAL COMPOSITIONS THEREOF
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The present invention relates to alkaloid aminoester derivatives acting as muscarinic receptor antagonists, processes for their preparation, compositions comprising them and therapeutic uses thereof.
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Page/Page column 33-34
(2012/01/13)
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- 4-PHENYL-1,3-THIAZOLES AND 4-PHENYL-1,3-OXAZOLES DERIVATIVES AS CANNABINOID RECEPTOR LIGANDS
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The present invention relates to new 4-phenyl-1,3-azole derivatives having the general formula (I) wherein R1, R2, R3, R4, X, A, B, and n are variable, in a racemic form, an enantiomeric form or any combinations thereof. These compounds exhibit affinity f
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Page/Page column 17
(2011/04/18)
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- Design and synthesis of novel hydantoin-containing melanin-concentrating hormone receptor antagonists
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We report here new chemical series acting as antagonists of melanin-concentrating hormone receptor 1 (MCHR-1). Synthesis and structure-activity relationships are described leading to the identification of compounds with optimized in vitro pharmacological and in vitro ADME profiles. In vivo activity has been demonstrated in animal models of food intake and depression.
- Balavoine, Fabrice,Malabre, Patrice,Alleaume, Thierry,Rey, Astrid,Cherfils, Valerie,Jeanneton, Olivier,Seigneurin-Venin, Sophie,Revah, Frederic
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p. 3754 - 3759
(2008/02/10)
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- Pyrrolo[2,3-d]pyrimidines containing an extended 5-substituent as potent and selective inhibitors of lck I
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Pyrrolo[2,3-d]pyrimidines containing a 5-(4-phenoxyphenyl) substituent are potent and selective inhibitors of lck in vitro; some compounds are selective for lck over src. Data are shown for two compounds demonstrating that they are potent and selective in
- Arnold, Lee D.,Calderwood, David J.,Dixon, Richard W.,Johnston, David N.,Kamens, Joanne S.,Munschauer, Rainer,Rafferty, Paul,Ratnofsky, Sheldon E.
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p. 2167 - 2170
(2007/10/03)
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