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.

نویسندگان

  • Philip Jones
  • Sergio Altamura
  • Julia Boueres
  • Federica Ferrigno
  • Massimiliano Fonsi
  • Claudia Giomini
  • Stefania Lamartina
  • Edith Monteagudo
  • Jesus M Ontoria
  • Maria Vittoria Orsale
  • Maria Cecilia Palumbi
  • Silvia Pesci
  • Giuseppe Roscilli
  • Rita Scarpelli
  • Carsten Schultz-Fademrecht
  • Carlo Toniatti
  • Michael Rowley
چکیده

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 IC(50) = 3.8 and 2.1 nM, respectively, and in a whole cell assay, it inhibited PARP activity with EC(50) = 4 nM and inhibited proliferation of cancer cells with mutant BRCA-1 and BRCA-2 with CC(50) 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.

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عنوان ژورنال:
  • Journal of medicinal chemistry

دوره 52 22  شماره 

صفحات  -

تاریخ انتشار 2009