TY - JOUR T1 - Pharmacological characterization of 1-(5-chloro-6-(trifluoromethoxy)-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid (JNJ-42041935), a potent and selective HIF prolyl hydroxylase (PHD) inhibitor JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.110.070508 SP - mol.110.070508 AU - Terrance D Barrett AU - Heather L Palomino AU - Theresa I Theresa I. Brondstetter AU - Kimon C Kanelakis AU - Xiaodong Wu AU - Peter V Haug AU - Wen Yan AU - Andy Young AU - Hong Hua AU - Juliet C Hart AU - Da-Thao Tran AU - Hariharan Venkatesan AU - Mark D Rosen AU - Hillary M Peltier AU - Kia Sepassi AU - Michele C Rizzolio AU - Scott D Bembenek AU - Tara Mirzadegan AU - Michael H Rabinowitz AU - Nigel P Shankley Y1 - 2011/01/01 UR - http://molpharm.aspetjournals.org/content/early/2011/03/03/mol.110.070508.abstract N2 - 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. ER -