Synthesis and structure-activity relationships of novel pyrrolocarbazole lactam analogs as potent and cell-permeable inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1)

Gregory J Wells; Ron Bihovsky; Robert L Hudkins; Mark A Ator; Jean Husten

doi:10.1016/j.bmcl.2005.11.086

Synthesis and structure-activity relationships of novel pyrrolocarbazole lactam analogs as potent and cell-permeable inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1)

Bioorg Med Chem Lett. 2006 Mar 1;16(5):1151-5. doi: 10.1016/j.bmcl.2005.11.086. Epub 2005 Dec 15.

Authors

Gregory J Wells¹, Ron Bihovsky, Robert L Hudkins, Mark A Ator, Jean Husten

Affiliation

¹ Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380-4245, USA. gwells@cephalon.com

PMID: 16359865
DOI: 10.1016/j.bmcl.2005.11.086

Abstract

A series of novel pyrrolocarbazole lactams was identified as potent PARP-1 inhibitors in vitro and in a PC12 cellular NAD(+) depletion assay. The SAR trends of substituents at the 3-position, as well as the effect of blocking the indole or lactam NH-groups of the template by methylation or formylation, are discussed in relation to molecular modeling studies.

MeSH terms

Animals
Carbazoles / chemical synthesis
Carbazoles / chemistry*
Carbazoles / pharmacology*
Cell Membrane Permeability / drug effects
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Imides / chemistry
Inhibitory Concentration 50
Lactams / chemical synthesis
Lactams / chemistry*
Lactams / pharmacology*
Models, Molecular
PC12 Cells
Poly(ADP-ribose) Polymerase Inhibitors*
Poly(ADP-ribose) Polymerases / chemistry
Poly(ADP-ribose) Polymerases / metabolism
Protein Structure, Tertiary
Pyrroles / chemical synthesis
Pyrroles / chemistry*
Pyrroles / pharmacology*
Rats
Structure-Activity Relationship

Substances

Carbazoles
Enzyme Inhibitors
Imides
Lactams
Poly(ADP-ribose) Polymerase Inhibitors
Pyrroles
Poly(ADP-ribose) Polymerases