Abstract
The hypoxia-inducible factor (HIF) prolyl hydroxylase (PHD) enzymes represent novel targets for the treatment of anemia, ulcerative colitis, and ischemic and metabolic disease inter alia. We have identified a novel small-molecule inhibitor of PHD, 1-(5-chloro-6-(trifluoromethoxy)-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid (JNJ-42041935), through structure-based drug design methods. The pharmacology of JNJ-42041935 was investigated in enzyme, cellular, and whole-animal systems and was compared with other compounds described in the literature as PHD inhibitors. JNJ-42041935, was a potent (pKI = 7.3–7.9), 2-oxoglutarate competitive, reversible, and selective inhibitor of PHD enzymes. In addition, JNJ-42041935 was used to compare the effect of selective inhibition of PHD to intermittent, high doses (50 μg/kg i.p.) of an exogenous erythropoietin receptor agonist in an inflammation-induced anemia model in rats. JNJ-42041935 (100 μmol/kg, once a day for 14 days) was effective in reversing inflammation-induced anemia, whereas erythropoietin had no effect. The results demonstrate that JNJ-42041935 is a new pharmacological tool, which can be used to investigate PHD inhibition and demonstrate that PHD inhibitors offer great promise for the treatment of inflammation-induced anemia.
Footnotes
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.110.070508.
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ABBREVIATIONS:
- HIF
- hypoxia-inducible factor
- PHD
- prolyl-4-hydroxylase
- 2-OG
- 2-oxoglutarate
- rhEPO
- recombinant human erythropoietin
- DMOG
- dimethyloxalylglycine
- 3,4-EDHB
- ethyl-3,4-dihydroxybenzoate
- JNJ-42041935
- 1-(5-chloro-6-(trifluoromethoxy)-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid
- FIH
- factor-inhibiting hypoxia-inducible factor
- PGPS
- peptidoglycan-polysaccharide polymers
- MCV
- mean corpuscular volume
- MCH
- mean cell hemoglobin.
- Received December 10, 2010.
- Accepted March 3, 2011.
- Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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