PT  - JOURNAL ARTICLE
AU  - Barrett, Terrance D.
AU  - Palomino, Heather L.
AU  - Brondstetter, Theresa I.
AU  - Kanelakis, Kimon C.
AU  - Wu, Xiaodong
AU  - Haug, Peter V.
AU  - Yan, Wen
AU  - Young, Andrew
AU  - Hua, Hong
AU  - Hart, Juliet C.
AU  - Tran, Da-Thao
AU  - Venkatesan, Hariharan
AU  - Rosen, Mark D.
AU  - Peltier, Hillary M.
AU  - Sepassi, Kia
AU  - Rizzolio, Michele C.
AU  - Bembenek, Scott D.
AU  - Mirzadegan, Tara
AU  - Rabinowitz, Michael H.
AU  - Shankley, Nigel P.
TI  - Pharmacological Characterization of 1-(5-Chloro-6-(trifluoromethoxy)-1<em>H</em>-benzoimidazol-2-yl)-1<em>H</em>-pyrazole-4-carboxylic Acid (JNJ-42041935), a Potent and Selective Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor
AID  - 10.1124/mol.110.070508
DP  - 2011 Jun 01
TA  - Molecular Pharmacology
PG  - 910--920
VI  - 79
IP  - 6
4099  - http://molpharm.aspetjournals.org/content/79/6/910.short
4100  - http://molpharm.aspetjournals.org/content/79/6/910.full
SO  - Mol Pharmacol2011 Jun 01; 79
AB  - 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.