159979-74-5Relevant articles and documents
Structure-based optimization of tyrosine kinase inhibitor CLM3. design, synthesis, functional evaluation, and molecular modeling studies.
Sartini, Stefania,Coviello, Vito,Bruno, Agostino,La Pietra, Valeria,Marinelli, Luciana,Simorini, Francesca,Taliani, Sabrina,Salerno, Silvia,Marini, Anna Maria,Fioravanti, Anna,Orlandi, Paola,Antonelli, Alessandro,Da Settimo, Federico,Novellino, Ettore,Bocci, Guido,La Motta, Concettina
, p. 1225 - 1235 (2014/03/21)
Recent advances in the knowledge of thyroid carcinomas development identified receptor tyrosine kinases, like VEGFR2 and RET, as viable and promising targets. Accordingly, their inhibition is emerging as the major therapeutic strategy to treat these pathologies. In this study we describe the synthesis and the functional evaluation of three different series of 4-substituted pyrazolo[3,4-d]pyrimidine derivatives, 8a-g, 9a-g, and 10a-g, designed exploiting a structure-based optimization of the previously developed inhibitor CLM3. Compared to the lead, the novel compounds markedly improved both their inhibitory profile against the target proteins, VEGFR2 and RET, and their antiproliferative efficacy against the medullary thyroid cancer cell line TT. Significantly, compounds 8b, 9c, and 10c proved to block the kinase activity of the mutant RETV804L, which still lacks effective inhibitors.
Does the combination of optimal substitutions at the C2-, N 5- and N8-positions of the pyrazolo-triazolo-pyrimidine scaffold guarantee selective modulation of the human A3 adenosine receptors?
Cheong, Siew Lee,Dolzhenko, Anton V.,Paoletta, Silvia,Lee, Evelyn Pei Rong,Kachler, Sonja,Federico, Stephanie,Klotz, Karl-Norbert,Dolzhenko, Anna V.,Spalluto, Giampiero,Moro, Stefano,Pastorin, Giorgia
scheme or table, p. 6120 - 6134 (2011/11/07)
In an attempt to study the optimal combination of a phenyl ring at the C2-position and different substituents at the N5- and N8-positions towards the selective modulation of human A3 adenosine receptors (hA3AR), we synthesized a new series of 2-para-(un)substituted-phenyl-pyrazolo-triazolo-pyrimidines bearing either a methyl or phenylethyl at N8 and chains of variable length at N 5. Through biological evaluation, it was found that the majority of the compounds had good affinities towards the hA3AR in the low nanomolar range. Compound 16 possessed the best hA3AR affinity and selectivity profile (KihA3 = 1.33 nM; hA 1/hA3 = 4880; hA2A/hA3 = 1100) in the present series of 2-(substituted)phenyl-pyrazolo-triazolo-pyrimidine derivatives. In addition to pharmacological characterization, a molecular modeling investigation on these compounds further elucidated the effect of different substituents at the pyrazolo-triazolo-pyrimidine scaffold on affinity and selectivity to hA3AR.
