- NOVEL HETEROCYCLIC DERIVATIVES WITH CARDIOMYOCYTE PROLIFERATION ACTIVITY FOR TREATMENT OF HEART DISEASES
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Provided are novel heterocyclic derivatives with cardiomyocyte proliferation activity for treatment of heart diseases. Specifically, provided are the compounds of formula (I) or pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs, prepa
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Page/Page column 20; 38
(2021/06/22)
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- Substitution at the indole 3 position yields highly potent indolecombretastatins against human tumor cells
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Resistance to combretastatin A-4 is mediated by metabolic modification of the phenolic hydroxyl and ether groups of the 3-hydroxy-4-methoxyphenyl (B ring). Replacement of the B ring of combretastatin A-4 by a N-methyl-5-indolyl reduces tubulin polymerization inhibition (TPI) and cytotoxicity against human cancer cell lines but cyano, methoxycarbonyl, formyl, and hydroxyiminomethyl substitutions at the indole 3-position restores potent TPI and cytotoxicity against sensitive human cancer cell lines. These highly potent substituted derivatives displayed low nanomolar cytotoxicity against several human cancer cell lines due to tubulin inhibition, as shown by cell cycle analysis, confocal microscopy, and tubulin polymerization inhibitory activity studies, and promoted cell killing mediated by caspase-3 activation. Binding at the colchicine site was suggested by molecular modeling studies. Substituted combretastatins displayed higher potencies than the isomeric isocombretastatins and the highest potencies were achieved for the hydroxyiminomethyl (21) and cyano (23) groups, with TPI values in the submicromolar range and cytotoxicities in the nanomolar and subnanomolar range. Dose-response and time-course studies showed that drug concentrations as low as 1 nM (23) or 10 nM (21) led to a complete G2/M cell cycle arrest after 15 h treatment followed by a high apoptosis-like cell response after 48–72 h treatment. The P-glycoprotein antagonist verapamil increased 21 and 23 cytotoxicity to IC50 values of 10?10 M, and highly potentiated the cytotoxic activity in 100-fold of the CHO derivative (17), in A-549 human non-small cell lung cancer cells. The cyano substituted indolecombretastatin 23 is by itself highly potent against rather resistant HT-29 and A-549 cell lines. A 3,4,5-trimethoxyphenyl ring always afforded more potent derivatives than a 2,3,4-trimethoxyphenyl ring.
- álvarez, Raquel,Gajate, Consuelo,Puebla, Pilar,Mollinedo, Faustino,Medarde, Manuel,Peláez, Rafael
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p. 167 - 183
(2018/09/18)
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- IMIDAZO [1,2-B] PYRIDAZINE DERIVATIVES FOR THE TREATMENT OF C-MET TYROSINE KINASE MEDIATED DISEASE
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The invention relates to compounds of formula (I) and salts thereof, formula (I) wherein the substituents are as defined in the specification, the application of a compound of formula (I) in a process for the treatment of the human or animal body, in particular with regard to C-Met tyrosine kinase mediated disease; the use of a compound of formula (I) for manufacturing a medicament for the treatment of such diseases; pharamaceutical compositions comprising a compound of the formula (I), optionally in the presence of a combination partner; processes for the preparation of a compound of formula (I).
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Page/Page column 72-73
(2009/10/21)
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- THIAZOLONES FOR USE AS PI3 KINASE INHIBITORS
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Invented is a method of inhibiting the activity/function of PI3 kinases using substituted thiazolones. Also invented is a method of treating one or more disease states selected from: autoimmune disorders, inflammatory diseases, cardiovascular diseases, ne
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- NOVEL CHEMICAL COMPOUNDS
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This invention relates to newly identified compounds for inhibiting hYAK3 proteins and methods for treating diseases associated with the imbalance or inappropriate activity of hYAK3 proteins.
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Page/Page column 40
(2010/02/13)
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- 4- (HETEROCYCLYL- FUSED PHENYL)- 3- (PHENYL OR PYRID -2- YL) PYRAZOLES AS INHIBITORS OF THE ALK-5- RECEPTOR
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The invention relates to novel pyrazole derivatives which are inhibitors of the transforming growth factor, ("TGF")-β signalling pathway, in particular, the phosphorylation of smad2 or smad3 by the TGF-β type I or activin-like kinase ("ALK")-5 receptor, m
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- COMPOUNDS
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The invention relates to novel aminothiazole derivatives which are inhibitors of the transforming growth factor, ("TGF")-? signaling pathway, in particular, the phosphorylation of smad2 or smad3 by the TGF-? type I or activin-like kinase ("ALK")-5 recepto
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Page/Page column 20-21
(2010/02/10)
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