Synthesis and biological evaluation of substituted 2-phenyl-2H-indazole-7-carboxamides as potent poly(ADP-ribose) polymerase (PARP) inhibitors |
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| Authors: | Rita Scarpelli Julia K Boueres Mauro Cerretani Federica Ferrigno Jesus M Ontoria Michael Rowley Carsten Schultz-Fademrecht Carlo Toniatti Philip Jones |
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| Institution: | IRBM—Merck Research Laboratories Rome, Via Pontina km 30,600, Pomezia 00040, Rome, Italy |
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| Abstract: | 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. |
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