title: Identification and SAR of novel pyrrolo[1,2-a]pyrazin-1(2H)-one derivatives as inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1).
abstract: 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.
authors.affiliation: IRBM/Merck Research Laboratories, 00040 Pomezia, Italy. giovanna.pescatore@gmail.com
authors.forename: Giovanna
authors.initials: G
authors.lastname: Pescatore
authors.forename: Danila
authors.initials: D
authors.lastname: Branca
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Fiore
authors.forename: Olaf
authors.initials: O
authors.lastname: Kinzel
authors.forename: Laura Llauger
authors.initials: LL
authors.lastname: Bufi
authors.forename: Ester
authors.initials: E
authors.lastname: Muraglia
authors.forename: Federica
authors.initials: F
authors.lastname: Orvieto
authors.forename: Michael
authors.initials: M
authors.lastname: Rowley
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 / 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
chemical_list: 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