product name MK-8245
Description: MK-8245 is a potent liver-targeting inhibitor of stearoyl-CoA desaturase (SCD) with IC50 of 1 nM for human SCD1 and 3 nM for both rat SCD1 and mouse SCD1, with anti-diabetic and anti-dyslipidemic efficacy and a significantly improved therapeutic window. When SCD inhibition has been measured by desaturation index in tissues of rodents treated with MK-8245, the desaturation index was significantly reduced in liver but not in other tissues such as skin, eye and adipose tissue.
References: J Med Chem. 2011 Jul 28;54(14):5082-96.
467.25
Formula
C17H16BrFN6O4
CAS No.
1030612-90-8
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 93 mg/mL (199.0 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Solubility (In vivo)
1% CMC+0.5% Tween-80: 30mg/mL
Synonyms
other peoduct :References PubMed ID：:http://www.ncbi.nlm.nih.gov/pubmed/19409938
| In Vitro |
In vitro activity: MK-8245, a phenoxy piperidine isoxazole derivative, has been identified as a potent and liver-specific SCD inhibitor. It contains a tetrazole acetic acid moiety, which is the key molecule for OATPs recognition and liver-targeting. MK-8245 displays similar potencies against human, rat and mouse SCD1 with IC50 values of 1 nM for human SCD1 and 3 nM for both rat SCD1 and mouse SCD1. MK-8245 exhibits a significant SCD inhibition in the rat hepatocyte assay which contains functional, active OATPs with IC50 of 68 nM, while being only weakly active in the HepG2 cell assay which is devoid of active OATPs with IC50 of ~1 μM. MK-8245 displays highly selective activity for the Δ-5 and Δ-6 desaturases (i.e., >100000 μM vs rat and human Δ5D and Δ6D as assessed in the HepG assay. Kinase Assay: The potency of MK-8245 against the stearoyl-CoA desaturase was determined by measuring the conversion of radiolabeled stearoyl-CoA to oleoyl-CoA using rat liver microsome or human SCDl (hSCD-1). Liver microsome was prepared from male Wistar or Spraque Dawley rats on a high carbohydrate diet for 3 days. The livers were homogenized (1:10 w/v) in a buffer containing 250 mM sucrose, 1 mM EDTA, 5 mM DTT and 50 mM Tris-HCl (pH 7.5). After a 100,000 × g centrifugation for 60 mins, the liver microsome pellet was suspended in a buffer containing 100 mM sodium phosphate, 20% glycerol, 2 mM DTT and stored at -78 °C. The human SCDl desaturase system was reconstituted using human SCDl from a baculovirus/Sf9 expression system, cytochrome B5 and cytochrome B5 reductase. Typically, different concentrations of MK-8245 in 2 μL DMSO was incubated for 15 mins at room temperature with 180 μL of the SCD enzyme in a buffer containing 100 mM Tris-HCl (pH 7.5), ATP (5 mM), Coenzyme-A (0.1 mM), Triton X-100 (0.5 mM) and NADH (2 mM). The reaction was initiated by the addition of 20 μL of [3H]-stearoyl-CoA (final concentration = 2 μM, radioactivity concentration = 1 μCi/mL). After 10 mins, the reaction mixture (80 μL) was mixed with a calcium chloride/charcoal aqueous suspension (100 μL charcoal (10% w/v) plus 25 μL CaCl2 (2N)). After centrifugation to precipitate the radioactive fatty acid species, tritiated water released from 9,10-[3H]-stearoyl-CoA by the SCD enzyme was quantified on a scintillation counter. Cell Assay: In the rat hepatocyte assay which contains functional and active OATPs, MK-8245 significantly inhibited SCD with an IC50 value of 68 nM. |
|---|---|
| In Vivo | Administration of MK-8245 at 10 mg/kg in mice exhibits a tissue distribution profile concentrated in the liver. It shows a liver-to-Harderian gland ratio of 21, suggesting a high degree of liver-targeting compared to a systemically distributed compound with liver-to-Harderian gland ratio of 1.5. Oral dosing of MK-8245 in mice, rats, dogs, and rhesus monkeys demonstrates that MK-8245 is distributed mainly to the liver, with low exposure in tissues associated with potential adverse events. The liver-to-skin ratios are >30:1 in all four species. Administration of MK-8245 to eDIO mice before the glucose challenge improves glucose clearance in a dose-dependent manner with ED50 of 7 mg/kg. |
| Animal model | Male C57/Bl6 mice |
| Formulation & Dosage | Suspended in 1% methocel in saline; 30mg/kg per day; oral gavage |
| References | J Med Chem. 2011 Jul 28;54(14):5082-96. |
