JNJ-42041935 was the most potent inhibitor of PHD2181–417 with a pIC50 value of 7.0 ± 0.03. JNJ-42041935 caused a concentration-dependent elevation of cellular HIF-1α and erythropoietin release in Hep3B cells. JNJ-42041935 (100 μmol/kg, once a day for 14 days) was effective in reversing inflammation-induced anemia.
|Cell lines||Hep3B cells|
|Preparation method||The potency of compounds for stabilization of intracellular HIF-1α and release of erythropoietin into the media was assessed in the human hepatoma cell line Hep3B. Cells were cultured in Dulbecco's modified Eagle's medium/high glucose (Invitrogen) supplemented with 10% fetal calf serum and 2 mM l-glutamine, 1% nonessential amino acids, 1 mM sodium pyruvate, 50 IU/ml penicillin, and 50 μg/ml streptomycin. A range of concentrations was incubated in 96-well plates with 30,000 cells/well for 24 h. Incubation media were collected, and cells were subsequently lysed for assessment of cellular HIF-1α content and erythropoietin concentration.|
|Concentrations||1 to 10 μM|
|Incubation time||24 h|
|Animal models||Balb/C mice|
|Dosages||30, 100, and 300 μmol/kg|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO: ≥ 30 mg/mL|
A role for prolyl hydroxylase domain proteins in hippocampal synaptic plasticity.
Corcoran A, et al. Hippocampus. 2013 Oct;23(10):861-72. PMID: 23674383.
Pharmacological characterization of 1-(5-chloro-6-(trifluoromethoxy)-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid (JNJ-42041935), a potent and selective hypoxia-inducible factor prolyl hydroxylase inhibitor.
Barrett TD, et al. Mol Pharmacol. 2011 Jun;79(6):910-20. PMID: 21372172.
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MK-8617 is an orally active pan-inhibitor of Hypoxia-inducible factor prolyl hydroxylase 1−3 (HIF PHD1−3), inhibiting PHD1, 2, 3 with IC50s of 1.0, 1.0 and 14 nM, respectively.
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