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. Daprodustat is a potent HIF-PH with IC50 values of 3.5 nM, 22.2 nM and 5.5 nM for PHD1, PHD2 and PHD3 (measured by FRET), respectively. Treatment with either 25 or 50 μM Daprodustat for 6h resulted in the accumulation of both HIF1α and HIF2α subunits in nuclear protein extracts of Hep3B cells. A single oral dose of GSK1278863 at 60 mg/kg resulted in EPO protein levels peaked at 12 hours post-dose, representing an 11.2-fold increase with a mean plasma concentration of 1303 pg/mL with minimal impact on VEGF concentrations in normal female B6D2F1 mice. Repeated daily treatment of normal B6D2F1 mice with Daprodustat at dose of 3, 10, or 30 mg/kg for 8 days, resulted in significant increases in reticulocytes, hemoglobin levels as well as red blood cell counts and hematocrit^[1]. Up to now, a phase 3 study to evaluate efficacy and safety of Daprodustat compared to Darbepoetin Alfa in Japanese Hemodialysis (HD)-Dependent Subjects with Anemia Associated with Chronic Kidney Disease (CKD) has been completed(see https://clinicaltrials.gov/).
• 作用机制Daprodustat can form tight binding interactions with the catalytic iron and a co-factor-pocket arginine residue of PHD.

• 动物研究
  剂量	Mice[1] (p.o.): 3 mg/kg - 60 mg/kg; rat[1] (p.o.): 10 mg/kg - 500 mg/kg
  给药途径	p.o.
  动物药代数据	Animal Rats[1] Dose 1.6 mg/kg (oral solution) 31.1 mg/kg (oral suspension) Administration p.o. Cmax 2.86 ± 0.51 μg/ml (solution) 62.40 ± 3.78 μg/ml (suspension) Tmax 4.0 h (solution) 2.0 h (suspension) AUC0-inf 106.63 ± 19.97 μg·h/ml (solution) AUC0→24h 46.61 ± 8.95 μg·h/ml (solution) 941.02 ± 68.91 μg·h/ml (suspension) DNAUC0-24h 29.13 μg·h/mL/mg/kg (solution) 30.26 μg·h/mL/mg/kg (suspension)