title: Identification of aminoethyl pyrrolo dihydroisoquinolinones as novel poly(ADP-ribose) polymerase-1 inhibitors.
abstract: 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.
authors: IRBM--Merck Research Laboratories Rome, Via Pontina km 30,600-Pomezia, 00040 Rome, Italy. danila_branca@merck.com
authors: Danila
authors: D
authors: Branca
authors: Mauro
authors: M
authors: Cerretani
authors: Philip
authors: P
authors: Jones
authors: Uwe
authors: U
authors: Koch
authors: Federica
authors: F
authors: Orvieto
authors: Maria Cecilia
authors: MC
authors: Palumbi
authors: Michael
authors: M
authors: Rowley
authors: Carlo
authors: C
authors: Toniatti
authors: Ester
authors: E
authors: Muraglia
mesh_terms: 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
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011108:Polymers; D015363:Quinolones