- Bioisosteric replacements of the indole moiety for the development of a potent and selective PI3Kδ inhibitor: Design, synthesis and biological evaluation
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Based on indole scaffold, a potent and selective phosphoinositide 3-kinase delta (PI3Kδ) inhibitor, namely FD223, was developed by the bioisosteric replacement drug discovery approach and studied for the treatment of acute myeloid leukemia (AML). In vitro
- Chen, Yi,Chen, Zhenxia,Deng, Mingli,Hong, Hui,Jia, Yu,Li, Qingquan,Li, Zhipeng,Ling, Yun,Liu, Xiaofeng,Lu, Mingzhu,Wu, Tianze,Xu, Chenyue,Yang, Chengbin,Yang, Yongtai,Zhou, Yaming
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supporting information
(2021/07/10)
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- Development of anti-breast cancer PI3K inhibitors based on 7-azaindole derivatives through scaffold hopping: Design, synthesis and in vitro biological evaluation
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Breast cancer is the cancer with the highest incidence all over the world. Phosphatidylinositol 3-kinase is an important regulator of intracellular signaling pathways, which is frequently mutated and overexpressed in majority of human breast cancers, and the inhibition of PI3K has been considered as a promising approach for the treatment of the cancer. Here, we report our design and synthesis of new 7-azaindole derivatives as PI3K inhibitors through the scaffold hopping strategy. By varying the groups at the 3-position of 7-azaindole, we identified a series of potent PI3K inhibitors, whose antiproliferative activities against two human breast cancer MCF-7 and MDA-MB-231 cell lines were evaluated. Representative derivatives FD2054 and FD2078 showed better activity than BKM120 in antiproliferation, reduced the levels of phospho-AKT and induced cell apoptosis. All these results suggested that FD2054 and FD2078 are potent PI3K inhibitors that could be considered as potential candidates for the development of anticancer agents.
- Chen, Yi,Deng, Mingli,Jia, Yu,Ling, Yun,Liu, Xiaofeng,Lu, Mingzhu,Qiu, Tianze,Xiang, Ruiqing,Yang, Chengbin,Yang, Yongtai,Zhou, Yaming
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supporting information
(2021/10/19)
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- Discovery of cinnoline derivatives as potent PI3K inhibitors with antiproliferative activity
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Cinnoline is a potential pharmacophore which has rarely been reported for uses as PI3K inhibitors. In this study, a series of cinnoline derivatives were developed as PI3K inhibitors and evaluated for enzymatic and cellular activities. Most compounds displ
- Chen, Yi,Deng, Mingli,Jia, Yu,Ling, Yun,Liu, Xiaofeng,Lu, Mingzhu,Tian, Chengze,Wu, Tianze,Yang, Chengbin,Yang, Yongtai,Zhou, Yaming
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supporting information
(2021/07/28)
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- Cnoline compound PI3K kinase inhibitor as well as preparation method and application thereof in pharmacy
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The invention provides a cinnoline compound PI3K kinase inhibitor as shown in a formula I. In the cinnoline compound PI3K kinase inhibitor, and R1, R2 and R3 are defined in the specification. The invention also provides a pharmaceutical composition of the
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Paragraph 0137-0139
(2021/06/02)
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- Discovery of 6′-chloro-N-methyl-5’-(phenylsulfonamido)-[3,3′-bipyridine]-5-carboxamide (CHMFL-PI4K-127) as a novel Plasmodium falciparum PI(4)K inhibitor with potent antimalarial activity against both blood and liver stages of Plasmodium
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Starting from a bipyridine-sulfonamide scaffold, medicinal chemistry optimization leads to the discovery of a novel Plasmodium falciparum PI4K kinase (PfPI4K) inhibitor compound 15g (CHMFL-PI4K-127, IC50: 0.9 nM), which exhibits potent activity against 3D7 Plasmodium falciparum (P. falciparum) (EC50: 25.1 nM). CHMFL-PI4K-127 displays high selectivity against PfPI4K over human lipid and protein kinase. In addition, it exhibits EC50 values of 23–47 nM against a panel of the drug-resistant strains of P. falciparum. In vivo, the inhibitor demonstrates the favorable pharmacokinetic properties in both rats and mice. Furthermore, oral administration of CHMFL-PI4K-127 exhibits the antimalaria efficacy in both blood stage (80 mg/kg) and liver stage (1 mg/kg) of Plasmodium in infected rodent model. The results suggest that CHMFL-PI4K-127 might be a new potential drug candidate for malaria.
- Liang, Xiaofei,Jiang, Zongru,Huang, Zhenghui,Li, Feng,Chen, Cheng,Hu, Chen,Wang, Wenliang,Hu, Zhenquan,Liu, Qingwang,Wang, Beilei,Wang, Li,Qi, Ziping,Liu, Jing,Jiang, Lubin,Liu, Qingsong
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- DUAL ATM AND DNA-PK INHIBITORS FOR USE IN ANTI-TUMOR THERAPY
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Provided herein are compounds of the Formula (I), (II), and (III), as well as pharmaceutically acceptable salts thereof, wherein the substituents are those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of oncologic diseases.
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Page/Page column 212; 213; 217
(2019/11/12)
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- Micro-reactor tandem synthesis method of indole anticancer drug molecules
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The invention relates to a micro-reactor tandem synthesis method of indole anticancer drug molecules. The method comprises the following steps: a reaction liquid 1 and a reaction liquid 2 are mixed, then are introduced into a first micro-reactor, and are reacted to obtain a first effluent, the first effluent and a reaction liquid 3 are mixed, then are introduced into a second micro-reactor, and are reacted to obtain a second effluent, the second effluent and a reaction liquid 4 are mixed, then are introduced into a third micro-reactor, and are reacted to obtain a final effluent, and the finaleffluent is concentrated and separated to obtain the indole anticancer drug molecules, wherein the reaction liquid 1 is a mixed solution containing 5-bromine-3-amino-2-substituted (R1)-pyridine, the reaction liquid 2 is substituted (R2)-benzenesulfonyl chloride, the reaction liquid 3 is a mixed solution containing bis(pinacolato)diboron, the reaction liquid 4 is a mixed solution containing a 5-bromo-7-azaindole derivative, and the indole anticancer drug molecules are benzenesulfonamidopyridylazaindole compounds. Compared with the prior art, the method of the invention has the advantages of high reaction efficiency, few side reactions and simple production process.
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Page/Page column 10-15; 23-26
(2019/12/08)
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- Discovery of a Novel Series of 7-Azaindole Scaffold Derivatives as PI3K Inhibitors with Potent Activity
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The phosphoinositide 3-kinase (PI3K) inhibitors potently inhibit the signaling pathway of PI3K/AKT/mTOR, which provides a promising new approach for the molecularly targeted cancer therapy. In this work, a novel series of 7-azaindole scaffold derivatives was discovered by the fragment-based growing strategy. The structure-activity relationship profiles identified that the 7-azaindole scaffold derivatives exhibit potent activity against PI3K at molecular and cellular levels as well as cell proliferation in a panel of human tumor cells.
- Yang, Chengbin,Zhang, Xi,Wang, Yi,Yang, Yongtai,Liu, Xiaofeng,Deng, Mingli,Jia, Yu,Ling, Yun,Meng, Ling-Hua,Zhou, Yaming
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supporting information
p. 875 - 880
(2017/08/16)
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- PI3K inhibitor, preparation method and application thereof in pharmacy
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The invention belongs to the technical field of pharmaceuticals and particularly relates to a PI3K inhibitor, a preparation method and application thereof in the pharmacy. The PI3K inhibitor is a compound of the structure shown by the general formula I or medically acceptable salt of the inhibitor. After the PI3K inhibitor is tested with a PI3K biochemical activity test method, the compound has excellent inhibitory activity to PI3K alpha and PI3K gamma, wherein the IC50 values of a plurality of compounds to the PI3K alpha and PI3K gamma reach nanomole grades (smaller than 100 nM). The result shows that the compounds can provide the inhibitor with better effectiveness and selectivity for curing PI3K-acted proliferative disease, and further a targeted drug for curing No. I type diabetes mellitus, lung disease, breast cancer, prostatic cancer, solid tumor, lymphoma, cardiovascular disease, rheumatoid arthritis, leukemia and the like can be hopefully developed. (Please see the general formula I in the description.).
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Paragraph 0095; 0096; 0097
(2016/12/26)
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- Optimization of Novel Indazoles as Highly Potent and Selective Inhibitors of Phosphoinositide 3-Kinase δ for the Treatment of Respiratory Disease
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Optimization of lead compound 1, through extensive use of structure-based design and a focus on PI3Kδ potency, isoform selectivity, and inhaled PK properties, led to the discovery of clinical candidates 2 (GSK2269557) and 3 (GSK2292767) for the treatment of respiratory indications via inhalation. Compounds 2 and 3 are both highly selective for PI3Kδ over the closely related isoforms and are active in a disease relevant brown Norway rat acute OVA model of Th2-driven lung inflammation.
- Down, Kenneth,Amour, Augustin,Baldwin, Ian R.,Cooper, Anthony W.J.,Deakin, Angela M.,Felton, Leigh M.,Guntrip, Stephen B.,Hardy, Charlotte,Harrison, Zo? A.,Jones, Katherine L.,Jones, Paul,Keeling, Suzanne E.,Le, Joelle,Livia, Stefano,Lucas, Fiona,Lunniss, Christopher J.,Parr, Nigel J.,Robinson, Ed,Rowland, Paul,Smith, Sarah,Thomas, Daniel A.,Vitulli, Giovanni,Washio, Yoshiaki,Hamblin, J. Nicole
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supporting information
p. 7381 - 7399
(2015/10/05)
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- NOVEL PYRIDOPYRIMIDINE DERIVATIVES AND USE THEREOF
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The invention provides novel substituted pyridopyrimidines represented by Formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, and a composition comprising these compounds. The compounds provided can be used as inhibitors of the phosphoinositide 3′ OH kinase family (PI3K) for the treatment of inflammatory diseases, cancer, cardiovascular diseases, allergy, asthma and autoimmune disorders.
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- BENZPYRAZOLE DERIVATIVES AS INHIBITORS OF P13 KINASES
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The invention is directed to certain novel compounds. Specifically, the invention is directed to compounds of formula (I) and salts thereof. The compounds of the invention are inhibitors of PI3-kinase activity.
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Page/Page column 83
(2011/06/25)
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- INDAZOLE DERIVATIVES AS PI 3 - KINASE INHIBITORS
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The invention is directed to certain novel compounds. Specifically, the invention is directed to compounds of formula (I) and salts thereof. The compounds of the invention are inhibitors of PI3-kinase activity.
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Page/Page column 68-69
(2011/06/25)
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- ORGANIC COMPOUNDS
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The present invention relates to a compound of formula (I) (I) or a salt thereof, wherein the substituents are as defined in the description, to compositions and use of the compounds in the treatment of diseases ameloriated by inhibition of phosphatidylinositol 3-kinase.
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Page/Page column 84-85
(2010/04/06)
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- PYRIDOSULFONAMIDE DERIVATIVES AS PI3 KINASE INHIBITORS
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Invented is a method of inhibiting the activity/function of PB kinases using pyridosulfonamide derivatives. Also invented is a method of treating one or more disease states selected from: autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, cancer, sperm motility, transplantation rejection, graft rejection and lung injuries by the administration of pyridosulfonamide derivatives.
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Page/Page column 53-54
(2009/05/30)
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- PYRIDOPYRIMIDINE DERIVATIVES AS PI3 KINASE INHIBITORS
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Invented is a method of inhibiting the activity/function of PB kinases using pyridoprimidine derivatives. Also invented is a method of treating one or more disease states selected from: autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, cancer, sperm motility, transplantation rejection, graft rejection and lung injuries by the administration of pyridopyrimidine derivatives.
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Page/Page column 49-50
(2009/04/25)
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- Organic compounds
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The present invention concerns a compound of formula (I) or a salt, suitably a pharmaceutically acceptable salt, or solvate thereof, wherein the groups R1, R2, Ar′, A and Y are defined in the description, to compositions and use of the compounds in the treatment of inflammatory and allergic conditions.
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Page/Page column 44
(2009/10/01)
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- 4-CARBOXAMIDE INDAZOLE DERIVATIVES USEFUL AS INHIBITORS OF P13-KINASES
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The invention is directed to certain novel compounds. Specifically, the invention is directed to compounds of formula (I) and salts thereof. The compounds of the invention are inhibitors of P13-kinase activity.
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Page/Page column 102
(2009/12/28)
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- QUINAZOLINE DERIVATIVES AS PI3 KINASE INHIBITORS
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Invented is a method of inhibiting the activity/function of P13 kinases using quinazoline derivatives. Also invented is a method of treating one or more disease states selected from: autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, cancer, sperm motility, transplantation rejection, graft rejection and lung injuries by the administration of quinazoline derivatives.
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- NAPHTHYRIDINE, DERIVATIVES AS P13 KINASE INHIBITORS
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Invented is a method of inhibiting the activity/function of PB kinases using naphthyridine derivatives. Also invented is a method of treating one or more disease states selected from: autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, cancer, sperm motility, transplantation rejection, graft rejection and lung injuries by the administration of naphthyridine derivatives.
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- QUINOXALINE DERIVATIVES AS PI3 KINASE INHIBITORS
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Invented is a method of inhibiting the activity/function of PI3 kinases using quinoxaline derivatives. Also invented is a method of treating one or more disease states selected from: autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, cancer, sperm motility, transplantation rejection, graft rejection and lung injuries by the administration of quinoxaline derivatives.
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Page/Page column 85-86
(2009/01/20)
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