RT Journal Article SR Electronic 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 FD American Society for Pharmacology and Experimental Therapeutics SP mol.110.070508 DO 10.1124/mol.110.070508 A1 Terrance D Barrett A1 Heather L Palomino A1 Theresa I Brondstetter A1 Kimon C Kanelakis A1 Xiaodong Wu A1 Peter V Haug A1 Wen Yan A1 Andy Young A1 Hong Hua A1 Juliet C Hart A1 Da-Thao Tran A1 Hariharan Venkatesan A1 Mark D Rosen A1 Hillary M Peltier A1 Kia Sepassi A1 Michele C Rizzolio A1 Scott D Bembenek A1 Tara Mirzadegan A1 Michael H Rabinowitz A1 Nigel P Shankley YR 2011 UL http://molpharm.aspetjournals.org/content/early/2011/03/10/mol.110.070508.abstract AB 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.