- Design, synthesis and biological evaluation of pyridone–aminal derivatives as MNK1/2 inhibitors
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Excessive phosphorylation of eukaryotic translation initiation factor 4E (eIF4E) plays a major role in the dysregulation of mRNA translation and the activation of tumor cell signaling. eIF4E is exclusively phosphorylated by mitogen-activated protein kinase interacting kinases 1 and 2 (MNK1/2) on Ser209. So, MNK1/2 inhibitors could decrease the level of p-eIF4E and regulate tumor-associated signaling pathways. A series of pyridone–aminal derivatives were synthesized and evaluated as MNK1/2 inhibitors. Several compounds exhibited great inhibitory activity against MNK1/2 and selected compounds showed moderate to excellent anti-proliferative potency against hematologic cancer cell lines. In particular, compound 42i (MNK1 IC50 = 7.0 nM; MNK2 IC50 = 6.1 nM) proved to be the most potent compound against TMD-8 cell line with IC50 value of 0.91 μM. Furthermore, 42i could block the phosphorylation level of eIF4E in CT-26 cell line, and 42i inhibited the tumor growth of CT-26 allograft model significantly. These results indicated that compound 42i was a promising MNK1/2 inhibitor for the potent treatment of colon cancer.
- Yuan, Xinrui,Wu, Hanshu,Bu, Hong,Zheng, Peiyuan,Zhou, Jinpei,Zhang, Huibin
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p. 1211 - 1225
(2019/02/28)
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- INHIBITORS OF THE RENAL OUTER MEDULLARY POTASSIUM CHANNEL
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The present invention provides compounds of Formula (I) and the pharmaceutically acceptable salts thereof, which are inhibitors of the ROMK (Kir1.1) channel. The compounds may be used as diuretic and/or natriuretic agents and for the therapy and prophylax
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Paragraph 0160
(2017/07/31)
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- Novel compounds
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The present invention relates to novel retinoid-related orphan receptor gamma (RORγ) modulators and their use in the treatment of diseases mediated by RORγ.
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Paragraph 0068
(2017/09/27)
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- HETEROCYCLIC COMPOUND
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The problem of the present invention is to provide a compound having a PDE2A inhibitory action, and useful as a prophylactic or therapeutic drug for schizophrenia, Alzheimer's disease and the like. The present invention relates to a compound represented by the formula (I): wherein each symbol is as described in the DESCRIPTION, or a salt thereof.
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Paragraph 0694
(2016/09/26)
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- Synthesis and Properties of a Novel Pyridineoxazoline Containing Optically Active Helical Polymer as a Catalyst Ligand for Asymmetric Diels-Alder Reaction
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A novel pyridineoxazoline (PyOx) containing helical polymer, poly{(-)-(S)-4-tert-butyl-2-[5-(4-tert-butylphenyl)-3-vinylpyridin-2-yl]-oxazoline} (PA), was designed and synthesized to approach the effect of chain conformation on the catalytic property. Its
- Wang, Heng,Li, Na,Zhang, Jie,Wan, Xinhua
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p. 523 - 531
(2015/08/03)
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- INHIBITORS OF THE RENAL OUTER MEDULLARY POTASSIUM CHANNEL
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The present invention provides compounds of Formula (I), and the pharmaceutically acceptable salts thereof, which are inhibitors of the ROMK (Kir1.1) channel. The compounds may be used as diuretic and/or natriuretic agents and for the therapy and prophyla
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Page/Page column 39
(2015/07/23)
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- INHIBITORS OF THE RENAL OUTER MEDULLARY POTASSIUM CHANNEL
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The present invention provides compounds of Formula (I) and the pharmaceutically acceptable salts thereof, which are inhibitors of the ROMK (Kir1.1) channel. The compounds may be used as diuretic and/or natriuretic agents and for the therapy and prophylax
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Page/Page column 41
(2015/07/23)
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- NOVEL COMPOUNDS
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The preseent invention relates to novel retinoid-related orphan receptor gamma(RORγ)modulators and their use in the treatment ofdiseases mediated by RORγ.
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Page/Page column 23
(2015/12/17)
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- NOVEL COMPOUNDS
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Disclosed are novel retinoid-related orphan receptor gamma (RORγ) modulators and their use in the treatment of diseases mediated by RORγ.
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Page/Page column 79
(2015/12/17)
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- AZAINDENOISOQUINOLINE TOPOISOMERASE I INHIBITORS
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The invention described herein pertains to substituted azaindenoisoquinoline compounds, in particular 7-, 8-, 9-, and 10-azaindenoisoquinoline compounds, which are inhibitors of topoisomerase I, processes and intermediates for their syntheses, pharmaceutical compositions of the compounds, and methods of using them in the treatment of cancer.
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- Pyridonaphthyridine PI3K/MTOR Dual Inhibitors and Preparation and Use Thereof
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The present invention relates to a pyridonaphthyridine compound as represented by general formula (I), which has a dual PI3K and mTOR inhibition effect, and its pharmaceutically acceptable salt, stereoisomer and deuteride thereof, wherein R1, R2, R3, R4, R5, R6, R7 and X are as defined in the specification; the present invention also relates to a method for preparing said compound, a pharmaceutical composition and a pharmaceutical formulation containing said compound, and uses of said compound in treating and/or preventing a proliferative disease and in the manufacture of a medicament for treating and/or preventing a proliferative disease.
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Page/Page column
(2014/04/17)
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- PYRIDONAPHTHYRIDINE PI3K/MTOR DUAL INHIBITORS AND PREPARATION AND USE THEREOF
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The present invention relates to a pyridonaphthyridine compound as represented by general formula (I), which has a dual PI3K and mTOR inhibition effect, and its pharmaceutically acceptable salt, stereoisomer and deuteride thereof, wherein R1, R2, R3, R4, R5, R6, R7 and X are as defined in the specification; the present invention also relates to a method for preparing said compound, a pharmaceutical composition and a pharmaceutical formulation containing said compound, and uses of said compound in treating and/or preventing a proliferative disease and in the manufacture of a medicament for treating and/or preventing a proliferative disease.
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Paragraph 0219-0221
(2014/05/07)
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- ISOINDOLINONE AND PYRROLOPYRIDINONE DERIVATIVES AS AKT INHIBITORS
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The present invention provides isoindolinone and pyrrolopyridinone derivatives, as well as their compositions and methods of use, that inhibit the activity of the serine/threonine kinase, Akt, and are useful in the treatment of diseases related to the act
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Paragraph 0388; 0389
(2013/04/24)
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- Azaindenoisoquinolines as topoisomerase i inhibitors and potential anticancer agents: A systematic study of structure-activity relationships
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A comprehensive study of a series of azaindenoisoquinoline topoisomerase I (Top1) inhibitors is reported. The synthetic pathways have been developed to prepare 7-, 8-, 9-, and 10-azaindenoisoquinolines. The present study shows that 7-azaindenoisoquinolines possess the greatest Top1 inhibitory activity and cytotoxicity. Additionally, the introduction of a methoxy group into the D-ring of 7-azaindenoisoquinolines improved their biological activities, leading to new lead molecules for further development. A series of QM calculations were performed on the model "sandwich" complexes of azaindenoisoquinolines with flanking DNA base pairs from the Drug-Top1-DNA ternary complex. The results of these calculations demonstrate how changes in two forces contributing to the π-π stacking (dispersion and charge-transfer interactions) affect the binding of the drug to the Top1-DNA cleavage complex and thus modulate the drug's Top1 inhibitory activity.
- Kiselev, Evgeny,Agama, Keli,Pommier, Yves,Cushman, Mark
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experimental part
p. 1682 - 1697
(2012/05/04)
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- AZA-ISOINDOLONES AND THEIR USE AS METABOTROPIC GLUTAMATE RECEPTOR POTENTIATORS - 613
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Compounds of formula I: wherein R1, R2, R3,R4, R5, R6, R7, R8 and n are defined in the specification, methods for using said compounds, methods for making said compoun
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Page/Page column 33
(2008/12/08)
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- Phthalazine, aza- and diaza-phthalazine compounds and methods of use
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The present invention comprises a new class of compounds useful for the prophylaxis and treatment of protein kinase mediated diseases, including inflammation and related conditions. The compounds have a general Formula I wherein A1, A2, B, R1, R2, R3 and R4 are defined herein. The invention also comprises pharmaceutical compositions including one or more compounds of Formula I, uses of such compounds and compositions for treatment of kinase mediated diseases including rheumatoid arthritis, psoriasis and other inflammation disorders, as well as intermediates and processes useful for the preparation of compounds of Formula I.
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Page/Page column 27
(2008/06/13)
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- Analogues of 1-(3,10-Dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]-cyclohepta[1, 2-b]pyridin-11-yl)piperidine as inhibitors of farnesyl protein transferase
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The synthesis of several 4-pyridylacetyl N-oxide derivatives of 4-(3-bromo-6,11-dihydro-5H-benzo[5,6]-cyclohepta[1,2-b]pyridin-11 -yl)piperazine/piperidine 3 is described. This study was aimed at identifying fomesyl protein transferase (FPT) inhibitors in these two series of tricycles containing different phenyl ring substituents. The in vitro activity profile of the initial group of compounds 7a-7g led to the synthesis of the 8-methyl-10-methoxy and 8-methyl-10-bromo analogues 7i, 13i, and 13j. The 11R(-) enantiomers of these compounds were found to exhibit potent in vitro FPT inhibition activity.
- Afonso, Adriano,Weinstein, Jay,Kelly, Joseph,Wolin, Ronald,Rosenblum, Stuart B.,Connolly, Michael,Guzi, Timothy,James, Linda,Carr, Donna,Patton, Robert,Bishop, W.Robert,Kirshmeier, Paul,Liu,Heimark,Chen,Nomeir
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p. 1845 - 1855
(2007/10/03)
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