Identification and SAR of novel pyrrolo[1,2-a]pyrazin-1(2H)-one derivatives as inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1).
Herein we describe the discovery of a novel series of pyrrolo[1,2-a]pyrazin-1(2H)-one PARP inhibitors. Optimization led to compounds that display excellent PARP-1 enzyme potency and inhibit the proliferation of BRCA deficient cells in the low double-digit nanomolar range showing excellent selectivity over BRCA proficient cancer cells.
Pescatore
Giovanna
G
IRBM/Merck Research Laboratories, 00040 Pomezia, Italy. giovanna.pescatore@gmail.com
Branca
Danila
D
Fiore
Fabrizio
F
Kinzel
Olaf
O
Bufi
Laura Llauger
LL
Muraglia
Ester
E
Orvieto
Federica
F
Rowley
Michael
M
Toniatti
Carlo
C
Torrisi
Caterina
C
Jones
Philip
P
D000818:Animals; D019313:BRCA1 Protein / Q000172:deficiency / Q000378:metabolism; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D006367:HeLa Cells; D006801:Humans; D007212:Indolizines / Q000737:chemistry / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D011719:Pyrazines / Q000737:chemistry* / Q000378:metabolism*; D051381:Rats; D013329:Structure-Activity Relationship
D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D007212:Indolizines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011719:Pyrazines; C035094:indolizine; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases