Discovery and SAR of novel, potent and selective hexahydrobenzonaphthyridinone inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1)

Caterina Torrisi; Monica Bisbocci; Raffaele Ingenito; Jesus M Ontoria; Michael Rowley; Carsten Schultz-Fademrecht; Carlo Toniatti; Philip Jones

doi:10.1016/j.bmcl.2009.12.002

Discovery and SAR of novel, potent and selective hexahydrobenzonaphthyridinone inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1)

Bioorg Med Chem Lett. 2010 Jan 15;20(2):448-52. doi: 10.1016/j.bmcl.2009.12.002. Epub 2009 Dec 4.

Authors

Caterina Torrisi¹, Monica Bisbocci, Raffaele Ingenito, Jesus M Ontoria, Michael Rowley, Carsten Schultz-Fademrecht, Carlo Toniatti, Philip Jones

Affiliation

¹ IRBM-Merck Research Laboratories Rome, Via Pontina km 30,600, Pomezia, 00040 Rome, Italy. [email protected]

PMID: 20015648
DOI: 10.1016/j.bmcl.2009.12.002

Abstract

A novel hexahydrobenzonaphthyridinone PARP-1 pharmacophore is reported, subsequent SAR exploration around this scaffold led to selective PARP-1 inhibitors with low nanomolar enzyme potency, displaying good cellular activity and promising rat PK properties.

MeSH terms

Animals
Drug Discovery
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacokinetics
Microsomes, Liver / metabolism
Naphthyridines / chemical synthesis
Naphthyridines / chemistry*
Naphthyridines / pharmacokinetics
Poly(ADP-ribose) Polymerase Inhibitors*
Poly(ADP-ribose) Polymerases / metabolism
Rats
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Naphthyridines
Poly(ADP-ribose) Polymerase Inhibitors
Poly(ADP-ribose) Polymerases