title: Phthalazinones. Part 1: The design and synthesis of a novel series of potent inhibitors of poly(ADP-ribose)polymerase.
abstract: Screening of the Maybridge compound collection identified 4-arylphthalazinones as micromolar inhibitors of PARP-1 catalytic activity. Subsequent optimisation of both inhibitory activity and metabolic stability led to a novel series of meta-substituted 4-benzyl-2H-phthalazin-1-ones with low nanomolar, cellular activity as PARP-1 inhibitors and promising metabolic stability in vitro.
authors.affiliation: KuDOS Horsham Ltd, 26 Foundry Lane, Horsham, West Sussex RH13 5PX, UK. vloh@kudospharma.co.uk
authors.forename: Vincent M
authors.initials: VM
authors.lastname: Loh
authors.forename: Xiao-ling
authors.initials: XL
authors.lastname: Cockcroft
authors.forename: Krystyna J
authors.initials: KJ
authors.lastname: Dillon
authors.forename: Lesley
authors.initials: L
authors.lastname: Dixon
authors.forename: Jan
authors.initials: J
authors.lastname: Drzewiecki
authors.forename: Penny J
authors.initials: PJ
authors.lastname: Eversley
authors.forename: Sylvie
authors.initials: S
authors.lastname: Gomez
authors.forename: Janet
authors.initials: J
authors.lastname: Hoare
authors.forename: Frank
authors.initials: F
authors.lastname: Kerrigan
authors.forename: Ian T W
authors.initials: IT
authors.lastname: Matthews
authors.forename: Keith A
authors.initials: KA
authors.lastname: Menear
authors.forename: Niall M B
authors.initials: NM
authors.lastname: Martin
authors.forename: Roger F
authors.initials: RF
authors.lastname: Newton
authors.forename: Jane
authors.initials: J
authors.lastname: Paul
authors.forename: Graeme C M
authors.initials: GC
authors.lastname: Smith
authors.forename: Julia
authors.initials: J
authors.lastname: Vile
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Whittle
mesh_terms: D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D007094:Imides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D010793:Phthalazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007094:Imides; D010793:Phthalazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1