Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 16, Issue 21, Pages 5687-5690Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2006.08.017
Keywords
prolyl hydroxylase inhibitors; HIFI-alpha; hypoxia; ischemia; peripheral arterial disease (PAD); anemia; pyrazolopyridines
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Recently resolved X-ray crystal structure of HIF-1 alpha prolyl hydroxylase was used to design and develop a novel series of pyrazolopyridines as potent HIF-1 alpha 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 mu M) to a potent (11I, 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-1 alpha. (c) 2006 Elsevier Ltd. All rights reserved.
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