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.
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.
Ferrigno
Federica
F
IRBM, Merck Research Laboratories Rome, Pomezia 00040, Rome, Italy. federica_ferrigno@libero.it
Branca
Danila
D
Kinzel
Olaf
O
Lillini
Samuele
S
Llauger Bufi
Laura
L
Monteagudo
Edith
E
Muraglia
Ester
E
Rowley
Michael
M
Schultz-Fademrecht
Carsten
C
Toniatti
Carlo
C
Torrisi
Caterina
C
Jones
Philip
P
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
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