| CAS NO: | 1187990-87-9 |
| 规格: | ≥98% |
| 包装 | 价格(元) |
| 5mg | 电议 |
| 10mg | 电议 |
| 25mg | 电议 |
| 50mg | 电议 |
| 100mg | 电议 |
| 250mg | 电议 |
| 500mg | 电议 |
Molecular Weight (MW) | 443.45 |
Formula | C24H21N5O4 |
CAS No. | 1187990-87-9 |
Storage | -20℃ for 3 years in powder form |
-80℃ for 2 years in solvent | |
Solubility (In vitro) | DMSO: 88 mg/mL (198.4 mM) |
Water:<1 mg/mL | |
Ethanol:<1 mg/mL | |
Solubility (In vivo) | O=C(C1=CN=C(C2=NN=CC=C2)N=C1O)NC(C3=CC=C(OC)C=C3)C4=CC=C(OC)C=C4 |
Synonyms | MK-8617; MK 8617; MK8617. |
In Vitro | In vitro activity: MK-8617 is a novel potent, selective, orally bioavailable pan-inhibitor of hypoxia-inducible factor prolyl hydroxylase 1–3 (HIF PHD1–3), which inhibits PHD1, 2, 3 with IC50 values of 1.0, 1.0 and 14 nM, respectively. MK-8617 is used for the treatment of anemia (10-19 hr dog and moneky t1/2). MK-8617 is not a significant inhibitor of the cytochrome p450 enzymes in vitro (IC50), CYP1A2, 3A4, 2B6, 2C9, 2C19, or 2D6,>60 μM, and is a moderate reversible inhibitor of CYP2C8 at 1.6 μM in vitro. MK-8617 is potent, selective, orally bioavailable across several species, and active in stimulating erythropoiesis. Mouse and rat studies showed hematological changes with elevations of plasma EPO and circulating reticulocytes following single oral dose administration, while 4-week q.d. po administration in rat elevated hemoglobin levels. MK-8617 has advanced to human clinical trials for anemia.
Kinase Assay: The catalytic activity assays for the HIF-PHD isoforms are performed at subsaturating levels of 2-oxoglutarate. To each well of a 96-well plate are added 1 μL of MK-8617 in DMSO and 20 μL of assay buffer containing 0.15 μg/mL FLAG-tagged full length HIF-PHD isoform expressed in and purified from baculovirus-infected Sf9 cells. After a 30 min preincubation at room temperature, the enzymatic reactions are initiated by the addition of 4 μL of substrates. After 2 h at room temperature, the reactions are terminated and signals are developed by the addition of a 25 μL quench/detection mix to a final concentration of 1 mM ortho-phenanthroline, 0.1 mM EDTA, 0.5 nM anti-(His)6 LANCE reagent, 100 nM AF647-labeled streptavidin, and 2 μg/mL (His)6-VHL complex. The ratio of time-resolved fluorescence signals at 665 and 620 nm is determined, and percent inhibition is calculated relative to an uninhibited control sample run in parallel.
Cell Assay: MK-8617 is not a significant inhibitor of the cytochrome p450 enzymes in vitro (IC50), CYP1A2, 3A4, 2B6, 2C9, 2C19, or 2D6,>60 μM, and is a moderate reversible inhibitor of CYP2C8 at 1.6 μM in vitro. MK-8617 is inactive when screened at 10 μM against a general panel of 171 radioligand binding and enzymatic assays. |
In Vivo | Tritiated MK-8617 exhibits minimal metabolic turnover in liver microsomes (+NADPH) from rat, dog, and monkey (<10% turover) but significant turnover in human liver microsomes (34% turnover) after 60 min (10 μM compound, 1 mg/mL microsomal protein). In terms of its pharmacokinetic profile, MK-8617 shows good oral bioavailability across species (36–71%), with low clearance and volume of distribution. The compound still has a relatively long elimination half-life across preclinical species. In mice (C57Bl/6), single doses of 5 and 15 mpk po (n = 3) causes increases in circulating reticulocytes measured on both 3 and 4 days postcompound challenge. In rat (Sprague–Dawley), a single dose titration of 1.5, 5, and 15 mpk po (n = 5) causes a large increase in serum erythropoietin(EPO) levels of 1.7-, 8-, and 204-fold relative to vehicle, respectively. Increases in circulating reticulocytes are observed at 5 and 15 mg/kg 3 days after challenge and, with the 15 mg dose, at 4 days after challenge. |
Animal model | C57Bl/6 mice |
Formulation & Dosage | Dissolved in DMSO/PEG400/water (5:40:55, v/v/v); 1 mg/kg po, 0.5 mg/kg iv; i.v. or p.o. |
References | J Med Chem. 2016 Dec 22;59(24):11039-11049. |
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