title: Phthalazinones 2: Optimisation and synthesis of novel potent inhibitors of poly(ADP-ribose)polymerase.
abstract: We have previously described the discovery of poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors based on a phthalazinone scaffold. Subsequent optimisation of inhibitory activity, metabolic stability and pharmacokinetic parameters has led to a novel series of meta-substituted 4-benzyl-2H-phthalazin-1-one PARP-1 inhibitors which retain low nM cellular activity and show good stability in vivo and efficacy in cell based models.
authors.affiliation: KuDOS Pharmaceuticals Ltd 327 Cambridge Science Park, Milton Road, Cambridge, CB4 0WG, UK. xcockcroft@kudospharma.co.uk
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: Frank
authors.initials: F
authors.lastname: Kerrigan
authors.forename: Vincent M
authors.initials: VM
authors.lastname: Loh
authors.forename: Niall M B
authors.initials: NM
authors.lastname: Martin
authors.forename: Keith A
authors.initials: KA
authors.lastname: Menear
authors.forename: Graeme C M
authors.initials: GC
authors.lastname: Smith
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; 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; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D010793:Phthalazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C499322:Parp1 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1