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

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 48 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.

Graphical abstractAn extensive SAR exploration of substituted 2-phenyl-2H-indazole-7-carboxamides is reported, resulting in the identification of 48 as a potent PARP inhibitor (IC50 = 4 nM), which inhibits the proliferation of BRCA1 deficient HeLa cells with CC50 = 42 nM, displays >15-fold selectivity over BRCA1 wild type cells and low clearance in rat after iv dosing.Figure optionsDownload full-size imageDownload as PowerPoint slide