Identification of substituted pyrazolo[1,5-a]quinazolin-5(4H)-one as potent poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors

Federica Orvieto; Danila Branca; Claudia Giomini; Philip Jones; Uwe Koch; Jesus M Ontoria; Maria Cecilia Palumbi; Michael Rowley; Carlo Toniatti; Ester Muraglia

doi:10.1016/j.bmcl.2009.05.113

Identification of substituted pyrazolo[1,5-a]quinazolin-5(4H)-one as potent poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors

Bioorg Med Chem Lett. 2009 Aug 1;19(15):4196-200. doi: 10.1016/j.bmcl.2009.05.113. Epub 2009 Jun 2.

Authors

Federica Orvieto¹, Danila Branca, Claudia Giomini, Philip Jones, Uwe Koch, Jesus M Ontoria, Maria Cecilia Palumbi, Michael Rowley, Carlo Toniatti, Ester Muraglia

Affiliation

¹ IRBM - Merck Research Laboratories Rome, Via Pontina km 30,600, Pomezia, 00040 Rome, Italy. federica_orvieto@merck.com

PMID: 19541484
DOI: 10.1016/j.bmcl.2009.05.113

Abstract

A novel series of pyrazolo[1,5-a]quinazolin-5(4H)-one derivatives proved to be a potent class of PARP-1 inhibitors. An extensive SAR around the 3-position of pyrazole in the scaffold led to the discovery of amides derivatives as low nanomolar PARP-1 inhibitors.

MeSH terms

Amides / chemistry
Chemistry, Organic / methods
Chemistry, Pharmaceutical / methods
Drug Design
Drug Evaluation, Preclinical
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / pharmacology
HeLa Cells
Humans
Inhibitory Concentration 50
Models, Chemical
Molecular Structure
Poly(ADP-ribose) Polymerase Inhibitors*
Pyrazoles / chemical synthesis*
Pyrazoles / pharmacology
Quinazolinones / chemical synthesis
Quinazolinones / pharmacology
Structure-Activity Relationship

Substances

Amides
Enzyme Inhibitors
Poly(ADP-ribose) Polymerase Inhibitors
Pyrazoles
Quinazolinones