RT Journal Article
SR Electronic
T1 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
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 910
OP 920
DO 10.1124/mol.110.070508
VO 79
IS 6
A1 Barrett, Terrance D.
A1 Palomino, Heather L.
A1 Brondstetter, Theresa I.
A1 Kanelakis, Kimon C.
A1 Wu, Xiaodong
A1 Haug, Peter V.
A1 Yan, Wen
A1 Young, Andrew
A1 Hua, Hong
A1 Hart, Juliet C.
A1 Tran, Da-Thao
A1 Venkatesan, Hariharan
A1 Rosen, Mark D.
A1 Peltier, Hillary M.
A1 Sepassi, Kia
A1 Rizzolio, Michele C.
A1 Bembenek, Scott D.
A1 Mirzadegan, Tara
A1 Rabinowitz, Michael H.
A1 Shankley, Nigel P.
YR 2011
UL http://molpharm.aspetjournals.org/content/79/6/910.abstract
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.