生物活性

• 描述The family of HIF-PH (HIF prolyl hydroxylase) enzymes are the main molecular to regulate HIF activity through hydroxylation at 2 proline residues and cause the degradation of HIF, thus leading to inhibition on accumulation of functional HIF under normoxia. Molidustat is a potent HIF-PH inhibitor with IC50 values of 480nM, 280nM and 450nM for PHD1, PHD2 and PHD3 (measured by the recombinant enzyme activity), respectively. Exposure of Molidustat up to 10uM for 2h led to increase of both HIF-1α and HIF-2α in a dose-dependent manner in HeLa, A549 and Hep3B cell lines, along with the increased transcriptional activity of HIF on gene, such as CA-IX, ANGPTL-4, GLUT-1, IGFBP-3, VEGF, Adrenomedullin and EPO. Daily administration of molidustat resulted in a dose-dependent increase of endogenous EPO production in preclinical studies. After a single oral administration of Molidustat at dose of 1.25-10mg/kg, EPO was significantly induced in male Wistar rats. Repeat treatment with Molidustat on dose of 1.25-5mg/kg resulted in a dose-dependent increase in mean packed cell volume. Similar effect of Molidustat on packed cell volume can be observed in the rat subtotal nephrectomy model as well as PG-PS-induced inflammatory anemia in female Lewis rats. Administration of Molidustat on dose of 2.5-10mg/kg for 7 days showed erythropoietic efficacy, with significant increase of hemoglobin, in renal and liver of rats with gentamicin-induced renal anemia^[1]. Molidustat is in recruiting I phase 3 trials for Anemia and Renal (see https://clinicaltrials.gov/).

• 动物研究
  剂量	Rat[1] (p.o.): 0.5 mg/kg - 10 mg/kg Monkey[1] (p.o.): 0.5 mg/kg, 1.5 mg/kg
  给药途径	p.o.