title: Development of substituted 6-[4-fluoro-3-(piperazin-1-ylcarbonyl)benzyl]-4,5-dimethylpyridazin-3(2H)-ones as potent poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors active in BRCA deficient cells.
abstract: We describe an extensive SAR study in the 6-[4-fluoro-3-(substituted)benzyl]-4,5-dimethylpyridazin-3(2H)-one series which led to the identification of potent PARP-1 inhibitors, capable of inhibiting the proliferation of BRCA-1 deficient cancer cells in the low nanomolar range, and displaying >100-fold selectivity over the BRCA wild type counterparts. The series of compounds was devoid of hERG channel activity, and CYP inhibition and induction liabilities. Several analogs were stable in rat and human liver microsomes and displayed moderate rat clearance, with urinary excretion of parent as the major route of elimination.
authors.affiliation: IRBM, Merck Research Laboratories Rome, Pomezia 00040, Rome, Italy. federica_ferrigno@libero.it
authors.forename: Federica
authors.initials: F
authors.lastname: Ferrigno
authors.forename: Danila
authors.initials: D
authors.lastname: Branca
authors.forename: Olaf
authors.initials: O
authors.lastname: Kinzel
authors.forename: Samuele
authors.initials: S
authors.lastname: Lillini
authors.forename: Laura
authors.initials: L
authors.lastname: Llauger Bufi
authors.forename: Edith
authors.initials: E
authors.lastname: Monteagudo
authors.forename: Ester
authors.initials: E
authors.lastname: Muraglia
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: Caterina
authors.initials: C
authors.lastname: Torrisi
authors.forename: Philip
authors.initials: P
authors.lastname: Jones
mesh_terms: D000818:Animals; D019313:BRCA1 Protein / Q000172:deficiency* / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010879:Piperazines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011724:Pyridazines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011724:Pyridazines; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases