Phthalazinones. Part 1: The design and synthesis of a novel series of potent inhibitors of poly(ADP-ribose)polymerase

Vincent M Loh Jr; Xiao-ling Cockcroft; Krystyna J Dillon; Lesley Dixon; Jan Drzewiecki; Penny J Eversley; Sylvie Gomez; Janet Hoare; Frank Kerrigan; Ian T W Matthews; Keith A Menear; Niall M B Martin; Roger F Newton; Jane Paul; Graeme C M Smith; Julia Vile; Alan J Whittle

doi:10.1016/j.bmcl.2005.03.026

Phthalazinones. Part 1: The design and synthesis of a novel series of potent inhibitors of poly(ADP-ribose)polymerase

Bioorg Med Chem Lett. 2005 May 2;15(9):2235-8. doi: 10.1016/j.bmcl.2005.03.026.

Authors

Vincent M Loh Jr¹, Xiao-ling Cockcroft, Krystyna J Dillon, Lesley Dixon, Jan Drzewiecki, Penny J Eversley, Sylvie Gomez, Janet Hoare, Frank Kerrigan, Ian T W Matthews, Keith A Menear, Niall M B Martin, Roger F Newton, Jane Paul, Graeme C M Smith, Julia Vile, Alan J Whittle

Affiliation

¹ KuDOS Horsham Ltd, 26 Foundry Lane, Horsham, West Sussex RH13 5PX, UK. vloh@kudospharma.co.uk

PMID: 15837300
DOI: 10.1016/j.bmcl.2005.03.026

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.

MeSH terms

Drug Design
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / pharmacology
Imides / chemical synthesis
Imides / chemistry
Imides / pharmacology
Kinetics
Models, Molecular
Molecular Structure
Phthalazines / chemical synthesis*
Phthalazines / chemistry
Phthalazines / pharmacology*
Poly (ADP-Ribose) Polymerase-1
Poly(ADP-ribose) Polymerase Inhibitors*
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Imides
Phthalazines
Poly(ADP-ribose) Polymerase Inhibitors
PARP1 protein, human
Poly (ADP-Ribose) Polymerase-1