ABSTRACT
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 (pK(I) = 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.
Subject(s)
Benzimidazoles/pharmacology , Enzyme Inhibitors/pharmacology , Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors , Procollagen-Proline Dioxygenase/antagonists & inhibitors , Pyrazoles/pharmacology , Amino Acid Sequence , Animals , Cell Line, Tumor , Female , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Mice , Molecular Sequence Data , Procollagen-Proline Dioxygenase/chemistry , Procollagen-Proline Dioxygenase/metabolism , Protein Binding , Rats , Rats, Inbred LewABSTRACT
Patients with long-term indwelling urinary catheters are at an increased risk for urinary tract infection due to bacteriuria. Catheter-associated urinary tract infections (CAUTIs) are a significant source of morbidity and mortality in long-term care facilities as well as in ambulatory patients requiring long-term catheterization. There is increased interest in the financial impact of CAUTI as Medicare no longer provides reimbursement for nosocomial CAUTIs. Ascending bacteria may in part enter the closed drainage system when the patient switches between leg and night collection bags. In an attempt to reduce this ascent, a double valve lock-out system was devised that maintains a closed system during bag exchange. The concept is introduced and CAUTIs are reviewed.