MK-8617 is a potent, selective, orally bioavailabl pan-inhibitor of hypoxia-inducible factor prolylhydroxylase 1−3 (HIF PHD1−3), inhibiting PHD1, 2, 3 with IC50s of 1.0, 1.0 and 14 nM, respectively.
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].
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