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

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.

Graphical abstractThe discovery and optimization of a novel series of pyrrolo[1,2-a]pyrazin-1(2H)-one PARP inhibitors is reported, leading to potent inhibitors displaying excellent anti-proliferation activity in BRCA deficient cells.Figure optionsDownload full-size imageDownload as PowerPoint slide