title: Synthesis and biological evaluation of substituted 2-phenyl-2H-indazole-7-carboxamides as potent poly(ADP-ribose) polymerase (PARP) inhibitors.
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 IC(50)=4nM, inhibited proliferation of cancer cell lines deficient in BRCA-1 with CC(50)=42nM and showed encouraging pharmacokinetic properties in rats compared to the lead 6.
authors.affiliation: IRBM-Merck Research Laboratories Rome, Via Pontina km 30,600, Pomezia 00040, Rome, Italy. rita.scarpelli@iit.it
authors.forename: Rita
authors.initials: R
authors.lastname: Scarpelli
authors.forename: Julia K
authors.initials: JK
authors.lastname: Boueres
authors.forename: Mauro
authors.initials: M
authors.lastname: Cerretani
authors.forename: Federica
authors.initials: F
authors.lastname: Ferrigno
authors.forename: Jesus M
authors.initials: JM
authors.lastname: Ontoria
authors.forename: Michael
authors.initials: M
authors.lastname: Rowley
authors.forename: Carsten
authors.initials: C
authors.lastname: Schultz-Fademrecht
authors.forename: Carlo
authors.initials: C
authors.lastname: Toniatti
authors.forename: Philip
authors.initials: P
authors.lastname: Jones
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001384:Azetidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: D000577:Amides; D000970:Antineoplastic Agents; D001384:Azetidines; D004791:Enzyme Inhibitors; D007191:Indazoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C111164:BRAP protein, human; D044767:Ubiquitin-Protein Ligases; D011065:Poly(ADP-ribose) Polymerases