| In Vitro | In vitro activity: Molidustat (formerly known as BAY 85-3934) is a novel potent inhibitor of hypoxia-inducible factor prolyl hydroxylase (HIF-PH) which stimulates erythropoietin (EPO) production and the formation of red blood cells. The mean IC50 values of BAY 85-3934 for PHD1, PHD2, and PHD3 are 480 nM, 280 nM, and 450 nM, respectively. HIF stabilization by oral administration of the HIF-PH inhibitor BAY 85-3934 (molidustat) resulted in dose-dependent production of EPO in healthy Wistar rats and cynomolgus monkeys. In repeat oral dosing of BAY 85-3934, hemoglobin levels were increased compared with animals that received vehicle, while endogenous EPO remained within the normal physiological range. BAY 85-3934 therapy was also effective in the treatment of renal anemia in rats with impaired kidney function and, unlike treatment with rhEPO, resulted in normalization of hypertensive blood pressure in a rat model of CKD. Notably, unlike treatment with the antihypertensive enalapril, the blood pressure normalization was achieved without a compensatory activation of the renin-angiotensin system. Thus, BAY 85-3934 may provide an approach to the treatment of anemia in patients with CKD, without the increased risk of adverse cardiovascular effects seen for patients treated with rhEPO. Clinical studies are ongoing to investigate the effects of BAY 85-3934 therapy in patients with renal anemia. Exposure of HeLa cells to 5 μM BAY 85-3934 for 20 min is sufficient to induce detectable concentrations of HIF-1α. In a cellular reporter assay, BAY 85-3934 induces the expression of the firefly luciferase reporter gene under the control of a hypoxia responsive element promoter at a mean (± SD) EC50 of 8.4±0.7 μM (n=4)
Kinase Assay: Molidustat (formerly known as BAY 85-3934) is a novel potent inhibitor of hypoxia-inducible factor prolyl hydroxylase (HIF-PH) which stimulates erythropoietin (EPO) production and the formation of red blood cells. The mean IC50 values of BAY 85-3934 for PHD1, PHD2, and PHD3 are 480 nM, 280 nM, and 450 nM, respectively.
Cell Assay: |
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| Animal model | Rats: BAY 85-3934 is prepared as a solution in ethanol:Solutol HS 15:water (10:20:70). In a repeat-dose, 26-day experiment, male Wistar rats (240–340 g in body weight) are administered vehicle or BAY 85-3934 at doses of 0.5 mg/kg, 1.25 mg/kg, 2.5 mg/kg, and 5 mg/kg. The efficacy of BAY 85-3934 (2.5 mg/kg, once-daily, oral) is also compared with that of rhEPO (25 IU/kg, 50 IU/kg, and 100 IU/kg, twice-weekly, s.c. injection). The time-course of induction of EPO mRNA expression and plasma EPO is determined at baseline and 0.5 h, 1 h, 2 h, 4 h, 6 h, and 8 h after oral administration of a single dose of BAY 85-3934 (5 mg/kg); Monkey: BAY 85-3934 is prepared as a solution in 0.5% tylose. Male and female cynomolgus monkeys (2.8–5.6 kg in body weight) are administered at doses of 0.5 mg/kg and 1.5 mg/kg at 0 h, 24 h, 48 h, 72 h, and 96 h. Blood samples are taken at 7 h, 31 h, 55 h, 79 h, 103 h, and 168 h. Erythropoietic parameters are also evaluated after a 2-week treatment period with s.c. administration of rhEPO (100 IU/kg twice weekly at days 1, 4, 8, and 11) and BAY 85-3934 (1.5 mg/kg) once daily |
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