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.
Physicochemical Properties
| Molecular Formula | C24H21N5O4 |
| Molecular Weight | 443.454644918442 |
| Exact Mass | 443.159 |
| CAS # | 1187990-87-9 |
| Related CAS # | 1187990-87-9 |
| PubChem CID | 44230662 |
| Appearance | White to off-white solid powder |
| LogP | 3.566 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 7 |
| Rotatable Bond Count | 7 |
| Heavy Atom Count | 33 |
| Complexity | 730 |
| Defined Atom Stereocenter Count | 0 |
| InChi Key | WXLPERVDMILVIF-UHFFFAOYSA-N |
| InChi Code | InChI=1S/C24H21N5O4/c1-32-17-9-5-15(6-10-17)21(16-7-11-18(33-2)12-8-16)27-23(30)19-14-25-22(28-24(19)31)20-4-3-13-26-29-20/h3-14,21H,1-2H3,(H,27,30)(H,25,28,31) |
| Chemical Name | N-[bis(4-methoxyphenyl)methyl]-6-oxo-2-pyridazin-3-yl-1H-pyrimidine-5-carboxamide |
| Synonyms | MK-8617; MK 8617; MK8617. |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| ln Vitro | With an IC50 of 1 nM for PHD2, MK-8617 is an oral active pan-inhibitor of hypoxia-inducible factor prolyl hydroxylase 1-3 (HIF PHD1-3). MK-8617 is a moderate reversible inhibitor of CYP2C8 at 1.6 μM in vitro and is not a significant inhibitor of cytochrome p450 enzymes (IC50), >60 μM. The inhibitor of HIF (FIH), MK-8617, was found to have an IC50 of 18 μM [1]. |
| ln Vivo | In rat, dog, and monkey liver microsomes, tritiated MK-8617 shows very little metabolic turnover (<10% turnover); however, in human liver, after 60 minutes (10 μM MK-8617, 1 mg/mL), it showed considerable turnover in microsomes (34% turnover of microsomal proteins). MK-8617 exhibits a low clearance and volume of distribution along with good oral bioavailability (36–71%) across species in terms of its pharmacokinetic profile. 48 hours following MK-8617 treatment, post-administration recovery of radioactivity was roughly 26% in bile, 12% in urine, and 38% in feces. This suggests that about 38% of MK-8617 was absorbed and eliminated into bile and urine, which is consistent with oral bioavailability (~36%) reported in rat studies. When administered intravenously, MK-8617 can also raise erythropoietin (EPO) levels, with a mouse MED of 1.5 mpk [1]. |
| Animal Protocol | C57Bl/6 mice; |
| References |
[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. J Med Chem. 2016 Dec 22;59(24):11039-11049. |
Solubility Data
| 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 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2550 mL | 11.2752 mL | 22.5505 mL | |
| 5 mM | 0.4510 mL | 2.2550 mL | 4.5101 mL | |
| 10 mM | 0.2255 mL | 1.1275 mL | 2.2550 mL |