802534-49-2Relevant academic research and scientific papers
Identification of potent pyrazolo[4,3-h]quinazoline-3-carboxamides as multi-cyclin-dependent kinase inhibitor
Traquandi, Gabriella,Ciomei, Marina,Ballinari, Dario,Casale, Elena,Colombo, Nicoletta,Croci, Valter,Fiorentini, Francesco,Isacchi, Antonella,Longo, Antonio,Mercurio, Ciro,Panzeri, Achille,Pastori, Wilma,Pevarello, Paolo,Volpi, Daniele,Roussel, Patrick,Vulpetti, Anna,Brasca, Maria Gabriella
experimental part, p. 2171 - 2187 (2010/08/19)
Abnormal proliferation mediated by disruption of the mechanisms that keep the cell cycle under control is a hallmark of virtually all cancer cells. Compounds targeting complexes between cyclin-dependent kinases (CDKs) and cyclins (Cy) and inhibiting their activity are regarded as promising antitumor agents to complement the existing therapies. An expansion of pyrazolo[4,3-h]quinazoline chemical class oriented to the development of three points of variability was undertaken leading to a series of compounds able to inhibit CDKs both in vitro and in vivo. Starting from the CDK selective but poorly soluble hit compound 1, we succeeded in obtaining several compounds showing enhanced inhibitory activity both on CDKs and on tumor cells and displaying improved physical properties and pharmacokinetic behavior. Our study led to the identification of compound 59 as a highly potent, orally bioavailable CDK inhibitor that exhibited significant in vivo efficacy on the A2780 ovarian carcinoma xenograft model. The demonstrated mechanisms of action of compound 59 on cancer cell lines and its ability to inhibit tumor growth in vivo render this compound very interesting as potential antineoplastic agent.
Identification of N,1,4,4-tetramethyl-8-{[4-(4-methylpiperazin-1-yl)phenyl] amino}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (PHA-848125), a potent, orally available cyclin dependent kinase inhibitor
Brasca, Maria Gabriella,Amboldi, Nadia,Ballinari, Dario,Cameron, Alexander,Casale, Elena,Cervi, Giovanni,Colombo, Maristella,Colotta, Francesco,Croci, Valter,D'Alessio, Roberto,Fiorentini, Francesco,Isacchi, Antonella,Mercurio, Ciro,Moretti, Walter,Panzeri, Achille,Pastori, Wilma,Pevarello, Paolo,Quartieri, Francesca,Roletto, Fulvia,Traquandi, Gabriella,Vianello, Paola,Vulpetti, Anna,Ciomei, Marina
experimental part, p. 5152 - 5163 (2010/03/04)
The discovery of a novel class of inhibitors of cyclin dependent kinases (CDKs) is described. Starting from compound 1, showing good potency as inhibitor of CDKs but being poorly selective against a panel of serine-threonine and tyrosine kinases, new analogues were synthesized. Enhancement in selectivity, antiproliferative activity against A2780 human ovarian carcinoma cells, and optimization of the physical properties and pharmacokinetic profile led to the identification of highly potent and orally available compounds. Compound 28 (PHA-848125), which in the preclinical xenograft A2780 human ovarian carcinoma model showed good efficacy and was well tolerated upon repeated daily treatments, was identified as a drug candidate for further development. Compound 28 is currently undergoing phase I and phase II clinical trials.
PYRAZOLO-QUINAZOLINE DERIVATIVES,PROCESS FOR THEIR PREPARATION AND THEIR USE AS KINASE INHIBITORS
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Page 91-92, (2008/06/13)
Pyrazolo-quinazoline derivatives of formula (Ia) or (Ib) 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 be useful, in therapy, in the treatment of diseases associated with a disregulated protein kinase activity, like cancer.
