Phthalazinones 2: Optimisation and synthesis of novel potent inhibitors of poly(ADP-ribose)polymerase

Xiao-Ling Cockcroft; Krystyna J Dillon; Lesley Dixon; Jan Drzewiecki; Frank Kerrigan; Vincent M Loh Jr; Niall M B Martin; Keith A Menear; Graeme C M Smith

doi:10.1016/j.bmcl.2005.10.081

Phthalazinones 2: Optimisation and synthesis of novel potent inhibitors of poly(ADP-ribose)polymerase

Bioorg Med Chem Lett. 2006 Feb 15;16(4):1040-4. doi: 10.1016/j.bmcl.2005.10.081. Epub 2005 Nov 15.

Authors

Xiao-Ling Cockcroft¹, Krystyna J Dillon, Lesley Dixon, Jan Drzewiecki, Frank Kerrigan, Vincent M Loh Jr, Niall M B Martin, Keith A Menear, Graeme C M Smith

Affiliation

¹ KuDOS Pharmaceuticals Ltd 327 Cambridge Science Park, Milton Road, Cambridge, CB4 0WG, UK. xcockcroft@kudospharma.co.uk

PMID: 16290932
DOI: 10.1016/j.bmcl.2005.10.081

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.

MeSH terms

Animals
Cell Proliferation / drug effects
Crystallography, X-Ray
Drug Design
Drug Evaluation, Preclinical
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Models, Molecular
Molecular Structure
Phthalazines / chemical synthesis*
Phthalazines / chemistry
Phthalazines / pharmacology*
Poly (ADP-Ribose) Polymerase-1
Poly(ADP-ribose) Polymerase Inhibitors*
Rats
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Phthalazines
Poly(ADP-ribose) Polymerase Inhibitors
Parp1 protein, rat
Poly (ADP-Ribose) Polymerase-1