Abstract
The HIF prolyl hydroxylase (PHD) enzymes represent novel targets for the treatment of anemia, ulcerative colitis, ischemic and metabolic disease inter alia. We have identified a novel small molecule inhibitor of PHD (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 to other compounds described in the literature as PHD inhibitors. JNJ-42041935, was a potent (pKI=7.3 to 7.9), 2-oxoglutarate competitive, reversible and selective inhibitor of PHD enzymes. In addition, JNJ-42401935 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.
- Received December 10, 2010.
- Revision received March 2, 2011.
- Accepted March 3, 2011.
- The American Society for Pharmacology and Experimental Therapeutics
