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MK-8617

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Chemical Structure| 1187990-87-9 同义名 : -
CAS号 : 1187990-87-9
货号 : A460721
分子式 : C24H21N5O4
纯度 : 99%+
分子量 : 443.455
MDL号 : MFCD22572348
存储条件：

粉末 Sealed in dry,2-8°C

液体 -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 5 mg/mL(11.28 mM)，配合低频超声助溶，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
动物实验配方：

IP 2% DMSO+2% Tween80+30% PEG300+water 0.4 mg/mL clear

PO 0.5% CMC-Na 36 mg/mL suspension

生物活性
靶点

  • PHD2

    PHD2, IC50:1 nM

  • PHD3

    PHD3, IC50:14 nM

  • PHD1

    PHD1, IC50:1 nM
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].
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

2.26mL

0.45mL

0.23mL

11.28mL

2.26mL

1.13mL

22.55mL

4.51mL

2.26mL
参考文献

[1]Discovery of N-[Bis(4-methoxyphenyl)methyl]-4-hydroxy-2-(pyridazin-3-yl)pyrimidine-5-carboxamide (MK-8617), an Orally Active Pan-Inhibitor of Hypoxia-Inducible Factor Prolyl Hydroxylase 1–3 (HIF PHD1–3) for the Treatment of Anemia

[2]Debenham JS, Madsen-Duggan C, et al. Discovery of N-[Bis(4-methoxyphenyl)methyl]-4-hydroxy-2-(pyridazin-3-yl)pyrimidine-5-carboxamide (MK-8617), an Orally Active Pan-Inhibitor of Hypoxia-Inducible Factor Prolyl Hydroxylase 1-3 (HIF PHD1-3) for the Treatment of Anemia. J Med Chem. 2016 Dec 22;59(24):11039-11049.