In vitro: 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 models||C57Bl/6 mice|
|Formulation||DMSO/PEG400/water (5:40:55, v/v/v)|
|Dosages||1 mg/kg po, 0.5 mg/kg iv|
|Administration||i.v or p.o|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||88 mg/mL in DMSO|
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.
Debenham JS, et al. J Med Chem. 2016 Dec 22;59(24):11039-11049. PMID: 28002958.
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