Novel alkoxybenzamide inhibitors of poly(ADP-ribose) polymerase

Keith A Menear; Claire Adcock; Francisco Cuenca Alonso; Kristel Blackburn; Louise Copsey; Jan Drzewiecki; Alexandra Fundo; Armelle Le Gall; Sylvie Gomez; Hashim Javaid; Carlos Fenandez Lence; Niall M B Martin; Chris Mydlowski; Graeme C M Smith

doi:10.1016/j.bmcl.2008.06.025

Novel alkoxybenzamide inhibitors of poly(ADP-ribose) polymerase

Bioorg Med Chem Lett. 2008 Jul 15;18(14):3942-5. doi: 10.1016/j.bmcl.2008.06.025. Epub 2008 Jun 12.

Authors

Keith A Menear¹, Claire Adcock, Francisco Cuenca Alonso, Kristel Blackburn, Louise Copsey, Jan Drzewiecki, Alexandra Fundo, Armelle Le Gall, Sylvie Gomez, Hashim Javaid, Carlos Fenandez Lence, Niall M B Martin, Chris Mydlowski, Graeme C M Smith

Affiliation

¹ KuDOS Pharmaceuticals Ltd, 410 Cambridge Science Park, Milton Road, Cambridge CB4 0PE, UK. [email protected]

PMID: 18579376
DOI: 10.1016/j.bmcl.2008.06.025

Abstract

We have previously described poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors based on a substituted benzyl-phthalazinone scaffold. As an alternative chemical template, a novel series of alkoxybenzamides were developed with restricted conformation through intramolecular hydrogen bond formation; the compounds exhibit low nM enzyme and cellular activity as PARP-1 inhibitors.

MeSH terms

Chemistry, Pharmaceutical
Drug Design
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
HeLa Cells
Humans
Hydrogen Bonding
Inhibitory Concentration 50
Models, Chemical
Molecular Conformation
Molecular Structure
Poly (ADP-Ribose) Polymerase-1
Poly(ADP-ribose) Polymerase Inhibitors*
Poly(ADP-ribose) Polymerases / chemistry
Structure-Activity Relationship
Substrate Specificity

Substances

Enzyme Inhibitors
Poly(ADP-ribose) Polymerase Inhibitors
PARP1 protein, human
PARP2 protein, human
Poly (ADP-Ribose) Polymerase-1
Poly(ADP-ribose) Polymerases