MK-8245

Biological Activity

MK-8245 is a highly potent liver-targeted stearoyl-CoA desaturase (SCD) inhibitor with an IC50 of 1 nM for human SCD1 enzyme. MK-8245 inhibits the SCD enzyme solely in the liver and not in other tissues for the following reasons. When SCD inhibition has been measured by desaturation index in tissues of rodents treated with MK-8245, the desaturation index is significantly decreased in liver but not in other tissues such as skin, eye and adipose tissue. MK-8245 is distributed primarily to the liver, with low exposure in tissues associated with potential adverse events. MK-8245 is significantly shifted in the non-OATP HepG2 cellular assay. MK-8245 should possess the desired lack of cell penetration. MK-8245 ameliorates glucose clearance dose-dependently to a similar extent with an ED50 of 7 mg/kg.

Protocol

Cell Experiment
Cell lines
Preparation method
Concentrations
Incubation time

Animal Experiment
Animal models	Male C57/Bl6 mice
Formulation	Suspended in 1% methocel in saline
Dosages	~30 mg/kg
Administration	Orally

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

Species	Mouse	Rat	Rabbit	Guinea pig	Hamster	Dog
Weight (kg)	0.02	0.15	1.8	0.4	0.08	10
Body Surface Area (m2)	0.007	0.025	0.15	0.05	0.02	0.5
Km factor	3	6	12	8	5	20

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 K_m factor for a mouse and then divide by the K_m factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Chemical Information