- Potent 2-[(pyrimidin-4-yl)amine}-1,3-thiazole-5-carbonitrile-based inhibitors of VEGFR-2 (KDR) kinase
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Pyrimidino-thiazolyl carbonitriles were prepared that are potent VEGFR-2 (KDR) kinase inhibitors. The modification of lead structures resulted in 3m which exhibited the best overall profile in KDR inhibitory activity, iv/po pharmacokinetics, and reduced hERG affinity.
- Sisko, John T.,Tucker, Thomas J.,Bilodeau, Mark T.,Buser, Carolyn A.,Ciecko, Patrice A.,Coll, Kathleen E.,Fernandes, Christine,Gibbs, Jackson B.,Koester, Timothy J.,Kohl, Nancy,Lynch, Joseph J.,Mao, Xianzhi,McLoughlin, Debra,Miller-Stein, Cynthia M.,Rodman, Leonard D.,Rickert, Keith W.,Sepp-Lorenzino, Laura,Shipman, Jennifer M.,Thomas, Kenneth A.,Wong, Bradley K.,Hartman, George D.
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Read Online
- Pyrimidine hydrazone derivative and preparation method and application thereof
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The invention relates to pyrimidine hydrazone derivatives as shown in a chemical structural formula I or II, pharmaceutically acceptable salts and pharmaceutical compositions thereof, and an application of the pyrimidine hydrazone derivatives and the pharmaceutically acceptable salts and the pharmaceutical compositions in preparation of influenza virus neuraminidase inhibitors, wherein X is selected from: fluorine, chlorine, bromine, hydroxyl, dihydroxy, 2-hydroxy-3-methoxy, 2-hydroxy-4-methoxy, 2-hydroxy-5-C1-C2 alkoxy, 2-hydroxy-6-C1-C2 alkoxy, 3-hydroxy-2-C1-C2 alkoxy, 3-hydroxy-4-C1-C2 alkoxy, 3-hydroxy-5-methyl C1-C2 alkoxy , 3-hydroxy-6-C1-C2 alkoxy, 4-hydroxy-2-C1-C2 alkoxy, 4-hydroxy-3-C1-C2 alkoxy, 4-hydroxy-3, 5-diC1-C2 alkoxy, trihydroxy or 4-hydroxy-3,5-dimethyl; and Y is selected from: fluorine, chlorine, bromine, acetamido, hydroxyl or methoxy.
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Paragraph 0078-0082
(2020/11/23)
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- Discovery of novel dual inhibitors of receptor tyrosine kinases EGFR and PDGFR-β related to anticancer drug resistance
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With ongoing resistance problems against the marketed EGFR inhibitors having a quinazoline core scaffold there is a need for the development of novel inhibitors having a modified scaffold and, thus, expected lower EGFR resistance problems. An additional problem concerning EGFR inhibitor resistance is an observed heterodimerization of EGFR with PDGFR-β that neutralises the sole inhibitor activity towards EGFR. We developed novel pyrimido[4,5-b]indoles with varied substitution patterns at the 4-anilino residue to evaluate their EGFR and PDGFR-β inhibiting properties. We identified dual inhibitors of both EGFR and PDGFR-β in the nanomolar range which have been initially screened in cancer cell lines to prove a benefit of both EGFR and PDGFR-β inhibition.
- Fischer, Tim,Najjar, Karim,Totzke, Frank,Sch?chtele, Christoph,Sippl, Wolfgang,Ritter, Christoph,Hilgeroth, Andreas
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- Discovery of wtRET and V804MRET Inhibitors: From Hit to Lead
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Oncogenic activation of RET kinase has been found in several neoplastic diseases, like medullary thyroid carcinoma, multiple endocrine neoplasia, papillary thyroid carcinoma, and non-small-cell lung cancer. Currently approved RET inhibitors were not originally designed to be RET inhibitors, and their potency against RET kinase has not been optimized. Hence, novel compounds able to inhibit both wild-type RET (wtRET) and its mutants (e.g., V804MRET) are needed. Herein we present the development and the preliminary evaluation of a new sub-micromolar wtRET/V804MRET inhibitor, N-(2-fluoro-5-trifluoromethylphenyl)-N′-{4′-[(2′′-benzamido)pyridin-4′′-ylamino]phenyl}urea (69), endowed with a 4-anilinopyridine structure, starting from our previously identified 4-anilinopyrimidine hit compound. Profiling against a panel of kinases indicated 69 as a multi cKIT/wtRET/V804MRET inhibitor.
- Mologni, Luca,Dalla Via, Martina,Chilin, Adriana,Palumbo, Manlio,Marzaro, Giovanni
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supporting information
p. 1390 - 1398
(2017/09/01)
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- BTK INHIBITOR
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Provided are a series of BTK inhibitors, and specifically disclosed are a compound, pharmaceutically acceptable salt thereof, tautomer thereof or prodrug thereof represented by formula (I), (II), (III) or (IV).
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Paragraph 0346-0347
(2017/11/16)
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- Integrating docking scores, interaction profiles and molecular descriptors to improve the accuracy of molecular docking: Toward the discovery of novel Akt1 inhibitors
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A set of forty-seven Akt1 inhibitors was used for the development of molecular docking based QSAR model by using nonlinear regression. The integration of docking scores, key interaction profiles and molecular descriptors remarkably improved the accuracy of the QSAR models, providing reasonable statistical parameters (Rtrain2 = 0.948, R test2 = 0.907 and Qcv2 = 0.794). The established MD-SVR model based structural modification of new 4-amino-pyrimidine derivatives was further performed, and six compounds 56a,b and 60a-d with good prediction activities were synthesized and biologically evaluated. All of these compounds exhibited promising Akt1 inhibitory and antiproliferative activities, suggesting the reliability and good application value of the established MD-SVR model in the development of Akt1 inhibitors.
- Zhan, Wenhu,Li, Daqiang,Che, Jinxin,Zhang, Liangren,Yang, Bo,Hu, Yongzhou,Liu, Tao,Dong, Xiaowu
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- Reaction kinetics in liquid ammonia up to 120°C: Techniques and some solvolysis and substitution reactions
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Liquid ammonia is known to be a useful solvent for aromatic nucleophilic substitution reactions of reactive aromatics. Most of the prior work has been carried out at atmospheric pressure and low temperatures. The purpose of this work is to extend the scope of these studies to less reactive haloaromatic substrates that require elevated temperatures to give useful reaction rates. Equipment has been developed to permit the safe study of reactions in liquid ammonia in small (5 mL) stainless steel tube reactors at temperatures up to 120°C (90 bar). Experimental techniques have been developed to permit meaningful sampling of solutions at high temperature and pressure. Sample capture into closed systems, either into a syringe containing quench solution, or directly into an HPLC sample loop, has been used to overcome problems due to flash precipitation and aerosol formation when sampling from high pressure. Activation parameters for the solvolysis of 4-fluoronitrobenzene have been determined over the temperature range 20° - 120°C, and the rates of solvolysis of 2-chloropyrimidine, 4,6-dichloropyrimidine and 2-chloro-5-trifluoromethylpyridine have been determined at appropriate temperatures. 2-Fluoropyridine is inert to solvolysis even at 120°C. Rates of some nucleophilic substitutions with sodium triazolate and sodium phenoxide have been measured. Useful selectivities towards nucleophilic substitution can be obtained for the reactions examined, and further work is planned to examine the wider scope of these reactions. Copyright 2013 John Wiley & Sons, Ltd. Equipment has been developed to permit the safe study of reactions in liquid ammonia in small (5 mL) stainless steel tube reactors at temperatures up to 120°C (90 bar). Activation parameters for the solvolysis of 4-fluoronitrobenzene have been determined over the temperature range 20° - 120°C, and the rates of solvolysis of 2-chloropyrimidine, 4,6-dichloropyrimidine and 2-chloro-5-trifluoromethylpyridine have been determined at appropriate temperatures. Rates of some aromatic nucleophilic substitutions with sodium triazolate and sodium phenoxide have been measured. Copyright
- Atherton, John H.,Page, Michael I.,Sun, Haifeng
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p. 1038 - 1043
(2014/01/06)
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- AZABENZOTHIAZOLE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
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Provided are compounds of Formula I, stereoisomers, tautomers, solvates, prodrugs and pharmaceutically acceptable salts thereof, wherein A, X, R1, R2, R4 and R5 are defined herein, a pharmaceutical composition that includes a compound of Formula I and a pharmaceutically acceptable carrier, adjuvant or vehicle, methods of using the compound or composition in therapy, and methods of 5 manufacturing a compound of Formula I
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Page/Page column 84
(2012/04/04)
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- SUBSTITUTED HYDROXAMIC ACIDS AND USES THEREOF
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This invention provides compounds of formula (I): wherein R1, R1b, R2a, R2b, R2c, and R2d have values as described in the specification, useful as inhibitors of HDAC6. The invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of using the compositions in the treatment of proliferative, inflammatory, infectious, neurological or cardiovascular diseases or disorders.
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Page/Page column 54
(2012/02/01)
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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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supporting information; experimental part
p. 7066 - 7083
(2011/12/04)
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- HETEROBICYCLIC CARBOXAMIDES AS INHIBITORS FOR KINASES
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The invention relates to novel compounds of formula (I) and their use in the treatment of the animal or human body, to pharmaceutical compositions comprising a compound of formula (I) and to the use of a compound of formula (I) for the preparation of pharmaceutical compositions for use in the treatment of protein kinase dependent diseases, especially of proliferative diseases, such as in particular tumour diseases.
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Page/Page column 52
(2010/11/28)
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- Treatment of bacterial induced diseases using DNA methyl transferase inhibitors
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Methods for treating and/or preventing disease conditions caused or induced or aggravated by microbes, especially bacteria, by inhibiting DNA methyltransferase activity, such as by administering to an animal a DNA methyltransferase inhibitor, are disclosed, along with methods of reducing or ablating virulence in bacteria by inhibiting DNA methyltransferase activity.
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Page/Page column 29
(2008/06/13)
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- IMIDAZOPYRIDINE AND IMIDAZOPYRIMIDINE DERIVATIVES AS ANTIBACTERIAL AGENTS
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Compounds of formula I and methods for their preparation are disclosed. Further disclosed are methods of making biologically active compounds of formula I as well as pharmaceutically acceptable compositions comprising compounds of formula I. Compounds of
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Page/Page column 35
(2008/06/13)
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- IDENTIFICATION OF KINASE INHIBITORS
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The invention concerns the identification of protein kinase inhibitors that preferentially bind to the inactive conformation of a target protein kinase. The inhibitors are identified by locking the target protein kinase in an inactive conformation, and us
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Page/Page column 67-70
(2008/06/13)
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- DNA Methyltransferase inhibitors
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A compound of the formula or a pharmaceutically acceptable salt thereof,whereinR1, R2, and R3 are the same or different and are independently hydrogen, lower alkyl, aryl or substituted aryl, lower alkoxy, lower alkoxyalkyl, or cycloalkyl or cycloalkyl alkoxy, where each cycloalkyl group has from 3-7 members, where up to two of the cycloalkyl members are optionally hetero atoms selected from oxygen and nitrogen, and where any member of the alkyl, aryl or cycloalkyl group is optionally substituted with halogen, lower alkyl or lower alkoxy, aryl or substituted aryl, andwhereR3 can be ribose, deoxyribose or phosphorylated derivatives thereof,whereinR1, R2, and R3 are not all hydrogen andwhereinwhen R3 is ribose, deoxyribose or phosphorylated derivatives thereof, one of R1 or R2 is not hydrogen.
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- Process for making substituted thiazolyl-amino pyrimidinyl
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The present invention relates to a process for preparing substituted thiazolyl-amino pyrimidinyl piperazines, which are capable of inhibiting, modulating and/or regulating signal transduction of both receptor-type and non-receptor type tyrosine kinases.
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Page/Page column 7
(2010/11/30)
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- Tyrosine kinase inhibitors
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The present invention relates to compounds which inhibit, regulate and/or modulate tyrosine kinase signal transduction, compositions which contain these compounds, and methods of using them to treat tyrosine kinase-dependent diseases and conditions, such as angiogenesis, cancer, tumor growth, atherosclerosis, age related macular degeneration, diabetic retinopathy, inflammatory diseases, and the like in mammals.
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