[Description]:
JNJ-42041935 is a potent, competitive and selective inhibitor of prolyl hydroxylase PHD; inhibits PHD1, PHD2, and PHD3 with pKi values of 7.91±0.04, 7.29 ±0.05, and 7.65±0.09, respectively.
[Related Catalog]:
[Target]
pKi: 7.91±0.04 (PHD1), 7.29 ±0.05 (PHD2), 7.65±0.09(PHD3)[1]
[In Vitro]
JNJ-42041935 is the most potent inhibitor of PHD2181–417 with a pIC50 value of 7.0±0.03. JNJ-42041935 also inhibits full-length PHD1, PHD2, andPHD3 enzymes (pKi values 7.91±0.04, 7.29 ±0.05, and 7.65±0.09, respectively) [1].
[In Vivo]
JNJ-42041935 is 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) is effective in reversing inflammation induced anemia, whereas erythropoietin has no effect. Administration of JNJ-42041935 (100 μmol/kg p.o.) for 5 consecutive days resulted in a 2-fold increase in reticulocytes, an increase in hemoglobin by 2.3 g/dl, and an increase in the hematocrit of 9%. Two hours after oral administration of 300 μmol/kg JNJ-42041935, the bioluminescence over the peritoneal area is increased by 2.2 ± 0.3-fold relative to luciferase-treated vehicle controls in the mouse [1].
[Kinase Assay]
The potency of JNJ-42041935 for inhibition of the structurally related enzyme FIH is assessed by methods similar to those described for PHD2. In brief, activity of FIH is determined using purified glutathione transferase-tagged full-length FIH amino acids 1 to 350 and a synthetic HIF-1α peptide corresponding to residues Asp788 to Leu822. Compounds are preincubated with 17.1 nM FIH for 30 min, followed by a 10-min incubation with 1 μM [2-14C]2-oxoglutarate, in the presence of 10 μM FeNH4SO4 in reaction buffer. The selectivity of JNJ-42041935 for inhibition of a range of other targets available for testing in commercial assays is also assessed at concentrations of 1 and 10 μM[1].
[Animal admin]
Mice: JNJ-42041935 is administered at doses of 30, 100, and 300 μmol/kg to Balb/C mice . Plasma is collected 6 h after the dose. Plasma erythropoietin concentration is measured. The hematological effects of JNJ-42041935 are assessed by administering the 100 μmol/kg dose on 5 consecutive days and collecting blood anticoagulated with EDTA on day 8 (3 days after the last dose)[1].
[References]
[Related Small Molecules]