Phthalazinones. Part 1: The design and synthesis of a novel series of potent inhibitors of poly(ADP-ribose)polymerase.
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.
Loh
Vincent M
VM
KuDOS Horsham Ltd, 26 Foundry Lane, Horsham, West Sussex RH13 5PX, UK. vloh@kudospharma.co.uk
Cockcroft
Xiao-ling
XL
Dillon
Krystyna J
KJ
Dixon
Lesley
L
Drzewiecki
Jan
J
Eversley
Penny J
PJ
Gomez
Sylvie
S
Hoare
Janet
J
Kerrigan
Frank
F
Matthews
Ian T W
IT
Menear
Keith A
KA
Martin
Niall M B
NM
Newton
Roger F
RF
Paul
Jane
J
Smith
Graeme C M
GC
Vile
Julia
J
Whittle
Alan J
AJ
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
D004791:Enzyme Inhibitors; D007094:Imides; D010793:Phthalazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1