- Design, synthesis, and biological evaluation of cyano-substituted 2,4-diarylaminopyrimidines as potent JAK3 inhibitors for the treatment of B-cell lymphoma
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A series of cyano-substituted 2,4-diarylaminopyrimidines was designed and synthesized as potent non-covalent JAK3 inhibitors. Among the derivatives synthesized, 9o (IC50 = 22.86 nM), 9 k (IC50 = 21.58 nM), and 9j (IC50 = 20.66 nM) demonstrated inhibitory potencies against JAK3 similar to the known JAK3 inhibitor tofacitinib (IC50 = 20.10 nM). Moreover, 9o displayed potent anti-proliferative activities against Raji and Ramos cells, with IC50 values of 0.9255 μM and 1.405 μM, respectively. In addition, 9o demonstrated low toxicity in normal HBE (human bronchial epithelial cells, IC50 > 10 μΜ) and L-02 (human liver cells, IC50 = 3.104 μΜ) cells. Analysis of the mode of action by flow cytometry indicated that 9o effectively arrested Raji cells at the G2/M phase. Taken together, these results suggested that 9o might be a promising candidate for development as a potential treatment for B-cell lymphoma.
- Chen, Lixue,Deng, Tuo,Jin, Yue,Li, Yanxia,Ma, Xiaodong,Wang, Changyuan,Wu, Bin,Xu, Youjun,Yang, Song,Yu, Jiawen
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- FGFR INHIBITOR AND APPLICATION THEREOF
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An azatricyclic compound (as represented by formula I) which acts as an inhibitor of fibroblast growth factor receptors (FGFR), as well as a pharmaceutical composition thereof, a preparation method, and a use therefor in the treatment of FGFR-mediated diseases. The azatricyclic compound exerts an effect by means of participating in the regulation of a plurality of processes such as cell proliferation, apoptosis, migration, neovascularization, and the like. AA%%%Formula (I).
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Paragraph 0097-0098
(2020/01/22)
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- Discovery and SARs of 5-Chloro- N4-phenyl- N2-(pyridin-2-yl)pyrimidine-2,4-diamine Derivatives as Oral Available and Dual CDK 6 and 9 Inhibitors with Potent Antitumor Activity
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Cyclin-dependent kinases (CDKs) are promising therapeutic targets for cancer therapy. Herein, we describe our efforts toward the discovery of a series of 5-chloro-N4-phenyl-N2-(pyridin-2-yl)pyrimidine-2,4-diamine derivatives as dual CDK6 and 9 inhibitors. Intensive structural modifications lead to the identification of compound 66 as the most active dual CDK6/9 inhibitor with balancing potency against these two targets and good selectivity over CDK2. Further biological studies revealed that compound 66 was directly bound to CDK6/9, resulting in suppression of their downstream signaling pathway and inhibition of cell proliferation by blocking cell cycle progression and inducing cellular apoptosis. More importantly, compound 66 significantly inhibited tumor growth in a xenograft mouse model with no obvious toxicity, indicating the promising therapeutic potential of CDK6/9 dual inhibitors for cancer treatment. Therefore, the above results are of great importance in the development of dual CDK6/9 inhibitors for cancer therapy.
- Wang, Yang,Chen, Xing,Yan, Yaoyao,Zhu, Xiaochen,Liu, Mingming,Liu, Xinhua
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p. 3327 - 3347
(2020/04/08)
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- Design, synthesis and biological evaluation of novel 7-amino-[1,2,4]triazolo[4,3-f]pteridinone, and 7-aminotetrazolo[1,5-f]pteridinone derivative as potent antitumor agents
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To develop novel therapeutic agents with anticancer activities, two series of novel 7-amino-[1,2,4]triazolo[4,3-f]pteridinone, and 7-aminotetrazolo[1,5-f]pteridinone derivatives were designed and synthesized. All compounds were tested for anti-proliferative activities against five cancer cell lines. The structure-activity relationships (SARs) studies were conducted through the variation in two regions, the moiety of A ring and the terminal aniline B on pteridinone core. 1-Methyl-1,2,4-triazole derivative L7 with 2,6-dimethylpiperazine showed the most potent antiproliferative activity against A549, PC-3, HCT116, MCF-7 and MDA-MB-231 cell lines with IC50 values of 0.16 μM, 0.30 μM, 0.51 μM, 0.30 μM, and 0.70 μM, respectively. Combined with the results of the molecular docking and enzymatic studies, the PLK1 was very likely to be one of the drug targets of compound L7. Furthermore, to clarify the anticancer mechanism of compound L7, further explorations in the bioactivity were conducted. The results showed that compound L7 obviously inhibited proliferation of A549 cell lines, induced a great decrease in mitochondrial membrane potential leading to apoptosis of cancer cells, suppressed the migration of tumor cells, and arrested G1 phase of A549 cells.
- Hou, Yunlei,Zhu, Liangyu,Li, Zhiwei,Shen, Qi,Xu, Qiaoling,Li, Wei,Liu, Yajing,Gong, Ping
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p. 690 - 709
(2019/01/04)
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- FUSED PYRIMIDINOPIPERIDINE DERIVATIVE, AND MANUFACTURING METHOD AND APPLICATION THEREOF
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The present invention relates to the fused pyrimidine piperidine cyclic derivative represented by the following formula (I) and a pharmaceutically acceptable salt thereof and a process for preparing the same, wherein R1, R2, R3
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Paragraph 0069-0071
(2019/04/25)
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- Design and synthesis of some new 1-phenyl-3/4-[4-(aryl/heteroaryl/alkyl-piperazine1-yl)-phenyl-ureas as potent anticonvulsant and antidepressant agents
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A series of 1-phenyl-3/4-[4-(aryl/heteroaryl/alkyl-piperazine1-yl)-phenyl-urea derivatives (29–42) were designed, synthesized and evaluated for their anticonvulsant activity by using maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ) seizure tests. The acute neurotoxicity was checked by rotarod assay. Most of the test compounds were found effective in both seizure tests. Compound 30 (1-{4-[4-(4-chloro-phenyl)-piperazin-1-yl]-phenyl}-3-phenyl-urea) exhibited marked anticonvulsant activity in MES as well as scPTZ tests. The phase II anticonvulsant quantification study of compound 30 indicates the ED50value of 28.5?mg/kg against MES induced seizures. In addition, this compound also showed considerable protection against pilocarpine induced status epilepticus in rats. Seizures induced by 3-mercaptopropionic acid model and thiosemicarbazide were significantly attenuated by compound 30, which suggested its broad spectrum of anticonvulsant activity. Interestingly, compound 30 displayed better antidepressant activity than standard drug fluoxetine. Moreover, compound 30 appeared as a non-toxic chemical entity in sub-acute toxicity studies.
- Mishra, Chandra Bhushan,Kumari, Shikha,Tiwari, Manisha
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p. 603 - 617
(2016/07/06)
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- Design and synthesis of new [1,2,3]triazolo[4,5-d]pyrimidine derivatives as potential antiproliferative agents
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A new series possessing [1,2,3]triazolo[4,5-d]pyrimidine scaffold was synthesized and biologically evaluated for potential antiproliferative activity. Fourteen compounds were selected for in vitro anticancer assay over a panel of 60 cell lines at National Cancer Institute (NCI), USA. The most sensitive cell lines to the synthesized compounds were leukemia (K-562 and SR), nonsmall cell lung cancer HOP-92, and melanoma MDA-MB- 435. Compounds 12 and 24 exerted broad spectrum activity against most cell panel, while compounds 14, 21, and 23 exhibited effectiveness toward specific cell lines belong to different tumor subpanels. Accordingly, SAR, COMPARE analyses, and in silico ADME profiling were discussed for the target compounds. In addition, compounds 11 and 22 exerted good FGFR3 inhibitory activity with 58.8 and 46.7% at 100 μM, respectively. Taken as a whole, the present study revealed that the new series can be considered as promising lead for further development of more potent anticancer agents as well as FGFR3 kinase potential inhibitors.
- Elkamhawy, Ahmed,Al-Sanea, Mohammad M.,Song, Chiman,Sim, Taebo,Roh, Eun Joo
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p. 1863 - 1873
(2015/07/15)
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- Design, synthesis and pharmacological evaluation of N-[4-(4-(alkyl/aryl/heteroaryl)-piperazin-1-yl)-phenyl]-carbamic acid ethyl ester derivatives as novel anticonvulsant agents
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A series of alkyl/aryl/heteroaryl piperazine derivatives (37-54) were designed and synthesized as potential anticonvulsant agents. The target compounds are endowed with satisfactory physicochemical as well as pharmacokinetic properties. The synthesized compounds were screened for their in vivo anticonvulsant activity in maximal electroshock (MES) and subcutaneous pentylenetetrazole (sc-PTZ) seizure tests. Further, neurotoxicity evaluation was carried out using rotarod method. Structure activity relationship studies showed that compounds possessing aromatic group at the piperazine ring displayed potent anticonvulsant activity. Majority of the compounds showed anti-MES activity whereas compounds 39, 41, 42, 43, 44, 50, 52, and 53 exhibited anticonvulsant activity in both seizure tests. All the compounds except 42, 46, 47, and 50 did not show neurotoxicity. The most active derivative, 45 demonstrated potent anticonvulsant activity in MES test at the dose of 30 mg/kg (0.5 h) and 100 mg/kg (4 h) and also delivered excellent protection in sc-PTZ test (100 mg/kg) at both time intervals. Therefore, compound 45 was further assessed in PTZ-kindling model of epilepsy which is widely used model for studying epileptogenesis. This compound was effective in delaying onset of PTZ-evoked seizures at the dose of 5 mg/kg in kindled animals and significantly reduced oxidative stress better than standard drug phenobarbital (PB). In result, compound 45 emerged as a most potent and safer anticonvulsant lead molecule.
- Kumari, Shikha,Mishra, Chandra Bhushan,Tiwari, Manisha
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supporting information
p. 1092 - 1099
(2015/02/19)
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- SUBSTITUTED PYRIMIDINES USEFUL AS EGFR-T790M KINASE INHIBITORS
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The present invention is directed to novel pyrimidines, their derivatives, pharmaceutically acceptable salts, solvates and hydrates thereof. The compounds and compositions of the present invention have protein kinases inhibitory activities and are expecte
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Page/Page column 16
(2015/09/23)
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- Design, synthesis and antitubercular evaluation of novel series of N-[4-(piperazin-1-yl)phenyl]cinnamamide derivatives
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The analogs of N-[4-(piperazin-1-yl)phenyl]cinnamamide were designed and synthesized by molecular hybridization approach in which part C of the designed molecule was linked through amide and carbamate functionality that improves the physicochemical properties and govern the pharmacokinetic and pharmacodynamic behavior. The systematic modification was done around the Part C to explore the structure activity relationship of antitubercular cinnamamide. All 52 compounds were evaluated for its antitubercular activity against Mycobacterium tuberculosis (M. tb) using Resazurin microtitre plate assay (REMA). Compound 11g with trifluoromethyl substitution exhibited good antitubercular activity of 3.125 μg/ml. The synthesized N-[4-(piperazin-1-yl)phenyl]cinnamamide derivatives showed promising activity against M. tb.
- Patel, Kavitkumar N.,Telvekar, Vikas N.
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- Discovery of 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl- piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea (NVP-BGJ398), A potent and selective inhibitor of the fibroblast growth factor receptor family of receptor tyrosine kinase
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A novel series of N-aryl-N′-pyrimidin-4-yl ureas has been optimized to afford potent and selective inhibitors of the fibroblast growth factor receptor tyrosine kinases 1, 2, and 3 by rationally designing the substitution pattern of the aryl ring. On the b
- Guagnano, Vito,Furet, Pascal,Spanka, Carsten,Bordas, Vincent,Le Douget, Micka?l,Stamm, Christelle,Brueggen, Josef,Jensen, Michael R.,Schnell, Christian,Schmid, Herbert,Wartmann, Markus,Berghausen, Joerg,Drueckes, Peter,Zimmerlin, Alfred,Bussiere, Dirksen,Murray, Jeremy,Graus Porta, Diana
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experimental part
p. 7066 - 7083
(2011/12/04)
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- CRYSTALLINE FORMS OF 3-(2,6-DICHLORO-3,5-DIMETHOXY-PHENYL)-1-{6-[4-(4-ETHYL-PIPERAZIN-1-YL)-PHENYLAMINO]-PYRIMIDIN-4-YL}-1-METHYL-UREA AND SALTS THEREOF.
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The present technology provides novel anhydrous and hydrated crystalline forms of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea, amorphous and anhydrous crystalline polymorphs of its mono
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Page/Page column 21-22
(2011/06/26)
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- Anti-prion activities and drug-like potential of functionalized quinacrine analogs with basic phenyl residues at the 9-amino position
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In this paper, we report the synthesis and cell-based anti-prion activity of quinacrine analogs derived by replacing the basic alkyl side chain of quinacrine with 4-(4-methylpiperazin-I-yl)phenyl, (1-benzylpiperidin-4-yl) and their structural variants. Several promising analogs were found that have a more favorable anti-prion profile than quinacrine in terms of potency and activity across different prion-infected murine cell models. They also exhibited greater binding affinities for a human prion protein fragment (hPrP121-231) than quinacrine, and had permeabilities on the PAMPA-BBB assay that fall within the range of CNS permeant candidates. When evaluated on bidirectional assays on a Pgp overexpressing cell line, one analog was less susceptible to Pgp efflux activity compared to quinacrine. Taken together, the results point to an important role for the substituted 9-amino side chain attached to the acridine, tetrahydroacridine and quinoline scaffolds. The nature of this side chain influenced cell-based potency, PAMPA permeability and binding affinity to hPrP121-231.
- Nguyen, Thuy,Sakasegawa, Yuji,Doh-Ura, Katsumi,Go, Mei-Lin
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experimental part
p. 2917 - 2929
(2011/07/08)
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- DERIVATIVES OF QUINOLINES AND QUINOXALINES AS PROTEIN TYROSINE KINASE INHIBITORS
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The invention relates to compounds of Formula (I), wherein the substituens are as defined in the specification, in free form or in the form of a pharmaceutically acceptable salt, solvate, ester, N-oxide thereof; processes for the preparation thereof; to p
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Page/Page column 67-68
(2009/12/27)
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- PYRIMIDINYL ARYL UREA DERIVATIVES BEING FGF INHIBITORS
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The invention relates to heteroaryl aryl ureas of the formula (IA), wherein the radicals and symbols have the meanings as defined herein, the use of such compounds in the treatment of protein kinase dependent diseases; to pharmaceutical preparations comprising said heteroaryl aryl ureas, to processes for the manufacture of such novel compounds and to methods of treatment comprising the use of such heteroaryl aryl ureas.
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Page/Page column 73
(2008/06/13)
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- PYRIMIDINE UREA DERIVATIVES AS KINASE INHIBITORS
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The invention relates to compounds of formula (I) wherein the substituents X1, R1, R2, R3 and R4 have the meaning as set forth and explained in the description of the invention, to processes for the preparation of these compounds, pharmaceutical compositions containing same, the use thereof optionally in combination with one or more other pharmaceutically active compounds for the therapy of a disease which responds to an inhibition of protein kinase activity, and a method for the treatment of such a disease.
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Page/Page column 210
(2008/06/13)
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- PHENYLACETAMIDES SUITABLE AS PROTEIN KINASE INHIBITORS
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The invention relates to compounds of the formula (I) wherein the moieties R1 , R2, R3, R9, R10 and Q and X, Y and Z are as defined in the specification, and salts thereof; as well as their use, methods of use for them and method of their synthesis, and the like. The compounds are protein kinase inhibitors and can, inter alia, be used in the treatment of various proliferative diseases.
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Page/Page column 84
(2008/06/13)
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- Substituted benzazoles and methods of their use as inhibitors of Raf kinase
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New substituted benz-azole compounds, compositions and methods of inhibition of Raf kinase activity in a human or animal subject are provided. The new compounds compositions may be used either alone or in combination with at least one additional agent for the treatment of a Raf kinase mediated disorder, such as cancer.
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