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CAS No.: 1187990-87-9

MK-8617 Catalog No. CSN19680

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

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400-920-2911

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纯度 & 质量文件批次:

靶点选择性

生物活性

实验方案

技术信息

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.
C_max	8.4 µM	11 µM	18 µM	17 µM
T_1/2	11 h	9.3 h	19 h	10 h
Vd_ss	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

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.

实验方案

计算器摩尔计算器总药量计算器工作液计算器
储存液制备
- 1 mg
- 5 mg
- 10 mg
- 1 mM
- 2.2550 mL
- 11.2751 mL
- 22.5502 mL
- 5 mM
- 0.4510 mL
- 2.2550 mL
- 4.5100 mL
- 10 mM
- 0.2255 mL
- 1.1275 mL
- 2.2550 mL

技术信息

CAS号

1187990-87-9

储存条件

粉末: Sealed in dry,2-8°C

液体: -20°C:3-6 月 -80°C:12月

分子式

C24H21N5O4

运输

蓝冰

分子量

443.45

别名

溶解度

DMSO	20.0 mg/mL (45.1 mM) warming
Water	insoluble

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

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靶点	Description	IC50
HIF PHD1		IC50:1nM
HIF PHD2		IC50:1nM
HIF PHD3		IC50:14nM

MK-8617 Catalog No. CSN19680

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