MK-8245

製品コードS1158 バッチS115801

印刷

化学情報

Chemical Structure Synonyms N/A Storage
(From the date of receipt)		 3 years -20°C powder
1 years -80°C in solvent
化学式

C17H16BrFN6O4
分子量 467.25 CAS No. 1030612-90-8
Solubility (25°C)* 体外 DMSO 93 mg/mL (199.03 mM)
Water Insoluble
Ethanol Insoluble
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

溶剤液（一定の濃度）を調合する

生物活性

製品説明 MK-8245 is an 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. Phase 2.
in vitro 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. [1]
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. [1]
特徴 A potent hepatic SCD inhibitor, and does not affect SCD enzyme in skin and eye tissues like other systemically distributed SCD inhibitors.

プロトコル(参考用のみ)

キナーゼアッセイ SCD1 enzyme activity assay
The potency of MK-8245 against the stearoyl-CoA desaturase is determined by measuring the conversion of radiolabeled stearoyl-CoA to oleoyl-CoA using rat liver microsome or human SCDl (hSCD-1). Liver microsome is prepared from male Wistar or Spraque Dawley rats on a high carbohydrate diet for 3 days. The livers are 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 x g centrifugation for 60 minutes, the liver microsome pellet is suspended in a buffer containing 100 mM sodium phosphate, 20% glycerol, 2 mM DTT and stored at -78 °C. The human SCDl desaturase system is 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 is incubated for 15 minutes 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 is initiated by the addition of 20 μL of [3H]-stearoyl-CoA (final concentration = 2 μM, radioactivity concentration = 1 μCi/mL). After 10 minutes, the reaction mixture (80 μL) is 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 is quantified on a scintillation counter.
動物実験 動物モデル Male C57/Bl6 mice
投薬量 ~30 mg/kg
投与方法 Orally

Selleckの高級品が、幾つかの出版された研究調査結果（以下を含む）で使われた：

YAP regulates an SGK1/mTORC1/SREBP-dependent lipogenic program to support proliferation and tissue growth [ Dev Cell, 2022, S1534-5807(22)00070-3] PubMed: 35216681
Rapid Alpha-Synuclein Toxicity in a Neural Cell Model and Its Rescue by a Stearoyl-CoA Desaturase Inhibitor [ Int J Mol Sci, 2020, 21(15):E5193] PubMed: 32707907
Dysregulated mTORC1 renders cells critically dependent on desaturated lipids for survival under tumor-like stress. [ Genes Dev, 2013, 27(10):1115-31] PubMed: 23699409

長期の保管のために-20°Cの下で製品を保ってください。

人間や獣医の診断であるか治療的な使用のためにでない。

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