Synthesis and biological evaluation of substituted 2-phenyl-2H-indazole-7-carboxamides as potent poly(ADP-ribose) polymerase (PARP) inhibitors

A potent series of substituted 2-phenyl-2H-indazole-7-carboxamides were synthesized and evaluated as inhibitors of poly (ADP-ribose) polymerase (PARP). This extensive SAR exploration culminated with the identification of substituted 5-fluoro-2-phenyl-2H-indazole-7-carboxamide analog 48 which display...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2010-01, Vol.20 (2), p.488-492
Main Authors: SCARPELLI, Rita, BOUERES, Julia K, CERRETANI, Mauro, FERRIGNO, Federica, ONTORIA, Jesus M, ROWLEY, Michael, SCHULTZ-FADEMRECHT, Carsten, TONIATTI, Carlo, JONES, Philip
Format: Article
Language:English
Subjects:
Amides - chemical synthesis
Amides - chemistry
Amides - pharmacology
Animals
Antineoplastic agents
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Azetidines - chemical synthesis
Azetidines - chemistry
Azetidines - pharmacology
Biological and medical sciences
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
General aspects
HeLa Cells
Humans
Indazoles - chemical synthesis
Indazoles - chemistry
Indazoles - pharmacology
Medical sciences
Pharmacology. Drug treatments
Poly(ADP-ribose) Polymerase Inhibitors
Poly(ADP-ribose) Polymerases - metabolism
Rats
Structure-Activity Relationship
Ubiquitin-Protein Ligases - deficiency
Ubiquitin-Protein Ligases - genetics
Ubiquitin-Protein Ligases - metabolism
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Summary:A potent series of substituted 2-phenyl-2H-indazole-7-carboxamides were synthesized and evaluated as inhibitors of poly (ADP-ribose) polymerase (PARP). This extensive SAR exploration culminated with the identification of substituted 5-fluoro-2-phenyl-2H-indazole-7-carboxamide analog 48 which displayed excellent PARP enzyme inhibition with IC(50)=4nM, inhibited proliferation of cancer cell lines deficient in BRCA-1 with CC(50)=42nM and showed encouraging pharmacokinetic properties in rats compared to the lead 6.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2009.11.127