@article {Barrettmol.110.070508, author = {Terrance D Barrett and Heather L Palomino and Theresa I Theresa I. Brondstetter and Kimon C Kanelakis and Xiaodong Wu and Peter V Haug and Wen Yan and Andy Young and Hong Hua and Juliet C Hart and Da-Thao Tran and Hariharan Venkatesan and Mark D Rosen and Hillary M Peltier and Kia Sepassi and Michele C Rizzolio and Scott D Bembenek and Tara Mirzadegan and Michael H Rabinowitz and Nigel P Shankley}, title = {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}, elocation-id = {mol.110.070508}, year = {2011}, doi = {10.1124/mol.110.070508}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, 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.}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/early/2011/03/03/mol.110.070508}, eprint = {https://molpharm.aspetjournals.org/content/early/2011/03/03/mol.110.070508.full.pdf}, journal = {Molecular Pharmacology} }