生物活性

• 靶点

  HIF PHD1 IC50:1nM

  HIF PHD2 IC50:1nM

  HIF PHD3 IC50:14nM

• 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. MK-8617 is a potent HIF-PH inhibitor with IC50 values of 1 nM, 1 nM and 14 nM for PHD1, PHD2 and PHD3, respectively. MK-8617 showed good oral bioavailability across species (36 - 71%), including mouse, rat, dog and rhesus, with low clearance and volume of distribution. Single dose of MK-8617, 5 and 15mpk, p.o., caused increases in circulating reticulocytes in mouse. A single dose titration of 1.5, 5 and 15mpk, p.o., caused a large increase in serum EPO levels ranging from 1.7, 8 and 204-fold relative to vehicle, respectively. Similar effect of MK-8617 can also be observed in rats. Repeat treatment with MK-8617, 1.5 and 15mpk, p.o., for 4 weeks resulted in 1.0 and a more extreme 7.6 g/dL change in Hb relative to vehicle treated rats^[1].
• 作用机制MK-8617 can form tight binding interactions with the catalytic iron and the primary binding pocket of PHD^[1].

• 动物研究
  剂量	Mice or rat[2] (p.o.): 1.5 mg/kg - 15 mg/kg
  给药途径	p.o.
  动物药代数据	Animal Mice[2] Rats[2] Dogs[2] Monkeys[2] Dose 1 mg/kg 0.5 mg/kg 2 mg/kg 1 mg/kg 1 mg/kg 0.5 mg/kg 1 mg/kg 0.5 mg/kg Administration p.o. i.v. p.o. i.v. p.o. i.v. p.o. i.v. Cmax 8.4 µM 11 µM 18 µM 17 µM T1/2 11 h 9.3 h 19 h 10 h Vdss 0.13 L/kg 0.16 L/kg 0.12 L/kg 0.10 L/kg PPB % unbound 0.6 1 0.5 F 0.63 0.36 0.71 0.52 CL 0.13 ml/min/kg 0.20 ml/min/kg 0.07 ml/min/kg 0.15 ml/min/kg