- NEW SUBSTITUTED AZAINDOLINE DERIVATIVES AS NIK INHIBITORS
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The present invention relates to pharmaceutical agents useful for therapy and/or prophylaxis in a mammal, and in particular to inhibitors of NF-κB-inducing kinase (NIK - also known as MAP3K14) useful for treating diseases such as cancer, inflammatory disorders, metabolic disorders and autoimmune disorders. The invention is also directed to pharmaceutical compositions comprising such compounds, and to the use of such compounds or pharmaceutical compositions for the prevention or treatment of diseases such as cancer, inflammatory disorders, metabolic disorders including obesity and diabetes, and autoimmune disorders.
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Page/Page column 132; 134; 135
(2019/01/21)
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- Discovery of novel 5-fluoro-N2,N4-diphenylpyrimidine-2,4-diamines as potent inhibitors against CDK2 and CDK9
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Based on a 3D-QSAR pharmacophore derived from a diverse set of known cyclin-dependent kinase 9 (CDK9) inhibitors and a composite pharmacophore extracted from the complex structure of flavopiridol (FVP)-CDK9, thirty novel 5-fluoro-N2,N4-diphenylpyrimidine-2,4-diamine derivatives were designed and synthesized. Initial tests against four tumor cell lines with the sulforhodamine B (SRB) assay identified a series of potent compounds with GI50 values at a lower micromolar or submicromolar level. Most of the highly cytotoxic compounds exhibited potent inhibitory activities against both CDK2/cyclin E1 and CDK9/cyclin T1. Notably, inhibitions against the two enzymes were generally correlated well with the cytotoxicity of these compounds. Appreciable inhibition was also observed for selected compounds in the anti-HIV-1 assay. Docking studies on compounds 6d and 9g provided conducive clues to further structural optimization. This journal is
- Gao, Jiadi,Fang, Cheng,Xiao, Zhiyan,Huang, Li,Chen, Chin-Ho,Wang, Li-Ting,Lee, Kuo-Hsiung
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p. 444 - 454
(2015/03/18)
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- Identification of 4,5-dihydro-1 H -pyrazolo[4,3- h ]quinazoline Derivatives as a new class of orally and selective polo-like kinase 1 inhibitors
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Polo-like kinase 1 (Plk1) is a fundamental regulator of mitotic progression whose overexpression is often associated with oncogenesis and therefore is recognized as an attractive therapeutic target in the treatment of proliferative diseases. Here we discuss the Structure-activity relationship of the 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline class of compounds that emerged from a high throughput screening (HTS) campaign as potent inhibitors of Plk1 kinase. Furthermore, we describe the discovery of 49, 8-{[2-methoxy-5-(4- methylpiperazin-1-yl)phenyl]amino}-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide, as a highly potent and specific ATP mimetic inhibitor of Plk1 (IC50 = 0.007 μM) as well as its crystal structure in complex with the methylated Plk136-345 construct. Compound 49 was active in cell proliferation against different tumor cell lines with IC 50 values in the submicromolar range and active in vivo in the HCT116 xenograft model where it showed 82% tumor growth inhibition after repeated oral administration.
- Beria, Italo,Ballinari, Dario,Bertrand, Jay Aaron,Borghi, Daniela,Bossi, Roberto Tiberio,Brasca, Maria Gabriella,Cappella, Paolo,Caruso, Michele,Ceccarelli, Walter,Ciavolella, Antonella,Cristiani, Cinzia,Croci, Valter,De Ponti, Anna,Fachin, Gabriele,Ferguson, Ronald Dale,Lansen, Jacqueline,Moll, Jurgen Karl,Pesenti, Enrico,Posteri, Helena,Perego, Rita,Rocchetti, Maurizio,Storici, Paola,Volpi, Daniele,Valsasina, Barbara
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experimental part
p. 3532 - 3551
(2010/09/11)
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- 2- [ (2-{PHENYLAMINO}-1H-PYRROLO [2, 3-D] PYRIMIDIN-4-YL) AMINO] BENZAMIDE DERIVATIVES AS IGF-1R INHIBITORS FOR THE TREATMENT OF CANCER
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Novel pyrrolopyrimidines as shown in formula (I) and pharmaceutically acceptable derivatives thereof. The compounds are useful in the inhibition of IGF-1R.
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Page/Page column 111-112
(2009/04/25)
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- SUBSTITUTED DIHYDROPTERIDIN-6-ONE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THEIR USE AS KINASE INHIBITORS
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Dihydropteridin-6-one derivatives of formula (I) as defined in the specification, and pharmaceutically acceptable salts thereof, process for their preparation and pharmaceutical compositions comprising them are disclosed; the compounds of the invention ma
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Page/Page column 23
(2009/07/17)
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- SUBSTITUTED PYRAZOLO-QUINAZOLINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THEIR USE AS KINASE INHIBITORS
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Pyrazolo-quinazoline derivatives of formula (I) as defined in the specification, and pharmaceutically acceptable salts thereof, process for their preparation and pharmaceutical compositions comprising them are disclosed; the compounds of the invention may
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Page/Page column 90
(2008/12/06)
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