Abstract
A new series of PHD (HIF prolyl 4-hydroxylase) inhibitors was designed based on the X-ray co-crystal structure of FG-2216. Using a lead generation process, a series of [(4-Hydroxyl-benzo[4,5]thieno[3,2-c]pyridine-3-carbonyl)-amino]-acetic acid derivatives was developed as potent PHD2 inhibitors. This class of compounds also showed the ability to stabilize HIF-α, to stimulate EPO secretion in in vitro studies, and to increase hematocrit, red blood cell count, and hemoglobin levels in an animal efficacy study.
Keywords:
Erythropoiesis; HIF-PH (PHD); Inhibitor; Stabilizer.
Copyright © 2013 Elsevier Ltd. All rights reserved.
MeSH terms
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Acetic Acid / chemistry*
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Acetic Acid / pharmacokinetics
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Acetic Acid / pharmacology*
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Animals
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Cell Line
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacokinetics
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Enzyme Inhibitors / pharmacology*
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Erythropoiesis / drug effects
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Erythropoietin / metabolism*
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
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Hypoxia-Inducible Factor-Proline Dioxygenases / antagonists & inhibitors*
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Hypoxia-Inducible Factor-Proline Dioxygenases / chemistry
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Hypoxia-Inducible Factor-Proline Dioxygenases / metabolism
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Male
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Models, Molecular
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Pyridines / chemistry
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Pyridines / pharmacokinetics
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Pyridines / pharmacology
Substances
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Enzyme Inhibitors
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Hypoxia-Inducible Factor 1, alpha Subunit
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Pyridines
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Erythropoietin
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Hypoxia-Inducible Factor-Proline Dioxygenases
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Acetic Acid