title: 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.
abstract: 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.
authors.affiliation: IRBM/Merck Research Labs Rome, Via Pontina km 30,600, 00040 Pomezia, Italy. philip_jones@merck.com
authors.forename: Philip
authors.initials: P
authors.lastname: Jones
authors.forename: Sergio
authors.initials: S
authors.lastname: Altamura
authors.forename: Julia
authors.initials: J
authors.lastname: Boueres
authors.forename: Federica
authors.initials: F
authors.lastname: Ferrigno
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Fonsi
authors.forename: Claudia
authors.initials: C
authors.lastname: Giomini
authors.forename: Stefania
authors.initials: S
authors.lastname: Lamartina
authors.forename: Edith
authors.initials: E
authors.lastname: Monteagudo
authors.forename: Jesus M
authors.initials: JM
authors.lastname: Ontoria
authors.forename: Maria Vittoria
authors.initials: MV
authors.lastname: Orsale
authors.forename: Maria Cecilia
authors.initials: MC
authors.lastname: Palumbi
authors.forename: Silvia
authors.initials: S
authors.lastname: Pesci
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Roscilli
authors.forename: Rita
authors.initials: R
authors.lastname: Scarpelli
authors.forename: Carsten
authors.initials: C
authors.lastname: Schultz-Fademrecht
authors.forename: Carlo
authors.initials: C
authors.lastname: Toniatti
authors.forename: Michael
authors.initials: M
authors.lastname: Rowley
mesh_terms: D000284:Administration, Oral; D000577:Amides / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D055808:Drug Discovery; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D009154:Mutation; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D010880:Piperidines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051381:Rats
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D007191:Indazoles; D010880:Piperidines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C545685:niraparib