title: Discovery and SAR of novel, potent and selective hexahydrobenzonaphthyridinone inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1).
abstract: A novel hexahydrobenzonaphthyridinone PARP-1 pharmacophore is reported, subsequent SAR exploration around this scaffold led to selective PARP-1 inhibitors with low nanomolar enzyme potency, displaying good cellular activity and promising rat PK properties.
authors.affiliation: IRBM-Merck Research Laboratories Rome, Via Pontina km 30,600, Pomezia, 00040 Rome, Italy. caterina.torrisi@addexpharma.com
authors.forename: Caterina
authors.initials: C
authors.lastname: Torrisi
authors.forename: Monica
authors.initials: M
authors.lastname: Bisbocci
authors.forename: Raffaele
authors.initials: R
authors.lastname: Ingenito
authors.forename: Jesus M
authors.initials: JM
authors.lastname: Ontoria
authors.forename: Michael
authors.initials: M
authors.lastname: Rowley
authors.forename: Carsten
authors.initials: C
authors.lastname: Schultz-Fademrecht
authors.forename: Carlo
authors.initials: C
authors.lastname: Toniatti
authors.forename: Philip
authors.initials: P
authors.lastname: Jones
mesh_terms: D000818:Animals; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D008862:Microsomes, Liver / Q000378:metabolism; D009287:Naphthyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D009287:Naphthyridines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases