1038915-56-8Relevant articles and documents
Discovery of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (MK-4827): A novel oral poly(ADP-ribose)polymerase (PARP) inhibitor efficacious in BRCA-1 and -2 mutant tumors
Jones, Philip,Altamura, Sergio,Boueres, Julia,Ferrigno, Federica,Fonsi, Massimiliano,Giomini, Claudia,Lamartina, Stefania,Monteagudo, Edith,Ontoria, Jesus M.,Orsale, Maria Vittoria,Palumbi, Maria Cecilia,Pesci, Silvia,Roscilli, Giuseppe,Scarpelli, Rita,Schultz-Fademrecht, Carsten,Toniatti, Carlo,Rowley, Michael
experimental part, p. 7170 - 7185 (2010/07/04)
We disclose the development of a novel series of 2-phenyl-2H-indazole-7- carboxamides as poly(ADP-ribose) polymerase (PARP) 1 and 2 inhibitors. This series was optimized to improve enzyme and cellular activity, and the resulting PARP inhibitors display antiproliferation activities against BRCA-1 and BRCA-2 deficient cancer cells, with high selectivity over BRCA proficient cells. Extrahepatic oxidation by CYP450 1A1 and 1A2 was identified as a metabolic concern, and strategies to improve pharmacokinetic properties are reported. These efforts culminated in the identification of 2-{4-[(3S)-piperidin-3-yl] phenyl}-2H-indazole-7-carboxamide 56 (MK-4827), which displays good pharmacokinetic properties and is currently in phase I clinical trials. This compound displays excellent PARP 1 and 2 inhibition with IC50 = 3.8 and 2.1 nM, respectively, and in a whole cell assay, it inhibited PARP activity with EC50 = 4 nM and inhibited proliferation of cancer cells with mutant BRCA-1 and BRCA-2 with CC50 in the 10-100 nM range. Compound 56 was well tolerated in vivo and demonstrated efficacy as a single agent in a xenograft model of BRCA-1 deficient cancer.
