Synthesis and biological evaluation of substituted 2-phenyl-2H-indazole-7-carboxamides as potent poly(ADP-ribose) polymerase (PARP) inhibitors.

By Scarpelli, Rita; Boueres, Julia K.; Cerretani, Mauro; Ferrigno, Federica; Ontoria, Jesus M.; Rowley, Michael; Schultz-Fademrecht, Carsten; Toniatti, Carlo; Jones, Philip
From Bioorganic & Medicinal Chemistry Letters (2010), 20(2), 488-492. Language: English, Database: CAPLUS, DOI:10.1016/j.bmcl.2009.11.127

A potent series of substituted 2-phenyl-2H-indazole-7-carboxamides were synthesized and evaluated as inhibitors of poly (ADP-ribose) polymerase (PARP). This extensive SAR exploration culminated with the identification of substituted 5-fluoro-2-phenyl-2H-indazole-7-carboxamide analog I which displayed excellent PARP enzyme inhibition with IC50 = 4 nM, inhibited proliferation of cancer cell lines deficient in BRCA-1 with CC50 = 42 nM and showed encouraging pharmacokinetic properties in rats compared to the lead 6.