Identification of aminoethyl pyrrolo dihydroisoquinolinones as novel poly(ADP-ribose) polymerase-1 inhibitors.
PARP inhibitors have been demonstrated to retard intracellular DNA repair and therefore sensitize tumor cells to cytotoxic agents or ionizing radiation. We report the identification of a novel class of PARP1 inhibitors, containing a pyrrolo moiety fused to a dihydroisoquinolinone, derived from virtual screening of the proprietary collection. SAR exploration around the nitrogen of the aminoethyl appendage chain of 1 led to compounds that displayed low nanomolar activity in a PARP1 enzymatic assay.
Branca
Danila
D
IRBM--Merck Research Laboratories Rome, Via Pontina km 30,600-Pomezia, 00040 Rome, Italy. danila_branca@merck.com
Cerretani
Mauro
M
Jones
Philip
P
Koch
Uwe
U
Orvieto
Federica
F
Palumbi
Maria Cecilia
MC
Rowley
Michael
M
Toniatti
Carlo
C
Muraglia
Ester
E
D000970:Antineoplastic Agents / Q000494:pharmacology; D001665:Binding Sites; D002626:Chemistry, Pharmaceutical / Q000379:methods; D018360:Crystallography, X-Ray / Q000379:methods; D004260:DNA Repair; D015195:Drug Design; D006801:Humans; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D008024:Ligands; D008956:Models, Chemical; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011108:Polymers / Q000737:chemistry; D015363:Quinolones / Q000737:chemistry*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D008024:Ligands; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011108:Polymers; D015363:Quinolones