A4345-5mg | MK-8245 [1030612-90-8] Clinisciences

Background

MK-8245 is a potent and liver-selective inhibitor of stearoyl-CoA desaturase (SCD) with IC50 value of 1nM [1].

SCD1 represents a therapeutic target for the treatment of type II diabetes, dyslipidemia, obesity, and metabolic diseases. As an inhibitor of SCD1, MK-8245 shows potency in both the rat enzyme and hepatocyte assay. There are no significant differences in potencies between the rat, mouse, and human SCD1. MK-8245 is developed as a liver-targeting SCD inhibitor. It demonstrates a liver-targeted tissue distribution profile resulting from a substrate recognition by organic anionic transporter proteins (OATPs) [1, 2].

MK-8245 is effective at lowering glucose level. It can improve glucose clearance dose-dependently with ED50 value of 7mg/kg. In the chronic eDIO mouse study, MK-8245 shows prevention of body weight gain with the maximally efficacious dose of 20 mg/kg bid based on body weight and liver triglyceride reduction [1].

Reference:
[1] Oballa RM, Belair L, Black WC, Bleasby K, Chan CC, Desroches C, Du X, Gordon R, Guay J, Guiral S, Hafey MJ, Hamelin E, Huang Z, Kennedy B, Lachance N, Landry F, Li CS, Mancini J, Normandin D, Pocai A, Powell DA, Ramtohul YK, Skorey K, Srensen D, Sturkenboom W, Styhler A, Waddleton DM, Wang H, Wong S, Xu L, Zhang L. Development of a liver-targeted stearoyl-CoA desaturase (SCD) inhibitor (MK-8245) to establish a therapeutic window for the treatment of diabetes and dyslipidemia. J Med Chem. 2011 Jul 28;54(14):5082-96.
[2] Lachance N, Guiral S, Huang Z, Leclerc JP, Li CS, Oballa RM, Ramtohul YK, Wang H, Wu J, Zhang L. Discovery of potent and liver-selective stearoyl-CoA desaturase (SCD) inhibitors in an acyclic linker series. Bioorg Med Chem Lett. 2012 Jan 1;22(1):623-7.

Chemical Properties

Physical Appearance	A solid
Storage	Store at -20°C
M.Wt	467.25
Cas No.	1030612-90-8
Formula	C17H16BrFN6O4
Solubility	≥23.35 mg/mL in DMSO; insoluble in EtOH; insoluble in H2O
Chemical Name	2-[5-[3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,2-oxazol-5-yl]tetrazol-2-yl]acetic acid
SDF	Download SDF
Canonical SMILES	C1CN(CCC1OC2=C(C=CC(=C2)F)Br)C3=NOC(=C3)C4=NN(N=N4)CC(=O)O
Shipping Condition	Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice.
General tips	We do not recommend long-term storage for the solution, please use it up soon.

Protocol

Kinase experiment [1]:
SCD1 enzyme activity 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 experiment [1]:
Cell lines	Rat hepatocytes
Preparation method	The solubility of this compound in DMSO is > 10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20 °C for several months.
Reaction Conditions	＜ 200 nM
Applications	In the rat hepatocyte assay which contains functional and active OATPs, MK-8245 significantly inhibited SCD with an IC50 value of 68 nM.
Animal experiment [1]:
Animal models	eDIO mice
Dosage form	3, 10 or 30 mg/kg; p.o.
Applications	MK-8245, a liver-targeted small molecule SCD inhibitor, improved whole body insulin sensitivity.
Other notes	Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
References: [1]. Oballa RM, Belair L, Black WC, Bleasby K, Chan CC, Desroches C, Du X, Gordon R, Guay J, Guiral S, Hafey MJ, Hamelin E, Huang Z, Kennedy B, Lachance N, Landry F, Li CS, Mancini J, Normandin D, Pocai A, Powell DA, Ramtohul YK, Skorey K, S?rensen D, Sturkenboom W, Styhler A, Waddleton DM, Wang H, Wong S, Xu L, Zhang L. Development of a liver-targeted stearoyl-CoA desaturase (SCD) inhibitor (MK-8245) to establish a therapeutic window for the treatment of diabetes and dyslipidemia. J Med Chem. 2011 Jul 28;54(14):5082-96.

Biological Activity

Description	MK-8245 is an liver-targeting inhibitor of stearoyl-CoA desaturase (SCD) with IC50 values of 1 nM, 3 nM and 3 nM for human, rat and mouse SCD1.
Targets	SCD1 (human)	SCD1 (rat)	SCD1 (mouse)
IC50	1 nM	3 nM	3 nM

Quality Control

Purity = 99.76%

Chemical structure

MK-8245 [1030612-90-8]

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