Identification and SAR of novel pyrrolo[1,2-a]pyrazin-1(2H)-one derivatives as inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1)

Giovanna Pescatore; Danila Branca; Fabrizio Fiore; Olaf Kinzel; Laura Llauger Bufi; Ester Muraglia; Federica Orvieto; Michael Rowley; Carlo Toniatti; Caterina Torrisi; Philip Jones

doi:10.1016/j.bmcl.2009.12.026

Identification and SAR of novel pyrrolo[1,2-a]pyrazin-1(2H)-one derivatives as inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1)

Bioorg Med Chem Lett. 2010 Feb 1;20(3):1094-9. doi: 10.1016/j.bmcl.2009.12.026. Epub 2009 Dec 6.

Authors

Giovanna Pescatore¹, Danila Branca, Fabrizio Fiore, Olaf Kinzel, Laura Llauger Bufi, Ester Muraglia, Federica Orvieto, Michael Rowley, Carlo Toniatti, Caterina Torrisi, Philip Jones

Affiliation

¹ IRBM/Merck Research Laboratories, 00040 Pomezia, Italy. [email protected]

PMID: 20031401
DOI: 10.1016/j.bmcl.2009.12.026

Abstract

Herein we describe the discovery of a novel series of pyrrolo[1,2-a]pyrazin-1(2H)-one PARP inhibitors. Optimization led to compounds that display excellent PARP-1 enzyme potency and inhibit the proliferation of BRCA deficient cells in the low double-digit nanomolar range showing excellent selectivity over BRCA proficient cancer cells.

Publication types

Comparative Study

MeSH terms

Animals
BRCA1 Protein / deficiency
BRCA1 Protein / metabolism
Cell Line, Tumor
Crystallography, X-Ray
HeLa Cells
Humans
Indolizines / chemistry
Indolizines / metabolism
Microsomes, Liver / drug effects
Microsomes, Liver / enzymology
Poly (ADP-Ribose) Polymerase-1
Poly(ADP-ribose) Polymerase Inhibitors*
Poly(ADP-ribose) Polymerases / metabolism
Protein Binding / physiology
Pyrazines / chemistry*
Pyrazines / metabolism*
Rats
Structure-Activity Relationship

Substances

BRCA1 Protein
BRCA1 protein, human
Indolizines
Poly(ADP-ribose) Polymerase Inhibitors
Pyrazines
indolizine
PARP1 protein, human
Poly (ADP-Ribose) Polymerase-1
Poly(ADP-ribose) Polymerases