Design and synthesis of a series of novel pyrazolopyridines as HIF 1-α prolyl hydroxylase inhibitors

Recently resolved X-ray crystal structure of HIF-1α prolyl hydroxylase was used to design and develop a novel series of pyrazolopyridines as potent HIF-1α prolyl hydroxylase inhibitors. The activity of these compounds was determined in a human EGLN-1 assay. Structure-based design aided in optimizing the potency of the initial lead (2, IC50 of 11 μM) to a potent (11l, 190 nM) EGLN-1 inhibitor. Several of these analogs were potent VEGF inducers in a cell-based assay. These pyrazolopyridines were also effective in stabilizing HIF-1α.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slide