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| 25mg |
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| 50mg |
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Purity: ≥98%
MK-5046 (MK5046) is a novel and potent Bombesin receptor subtype-3 (BRS-3) agonist with anti-obesity effect. It has a strong affinity (mouse Ki = 1.6 nM, human Ki = 25 nM) for BRS-3. An orphan G protein-coupled receptor involved in the control of energy homeostasis is called bombesin receptor subtype-3 (BRS-3). Single oral doses of MK-5046 increased the metabolic rate during fasting and inhibited food intake for two hours and overnight in wild-type mice, but not in Brs3 knockout mice. MK-5046, administered at a dose of 25 mg kg(-1) · day(-1) for 14 days, caused a 9% reduction in body weight in diet-induced obese mice when compared to vehicle-dosed controls. 50% brain receptor occupancy was attained in mice at 0.34 ± 0.23 μM for plasma concentration. Effects on metabolic rate, as opposed to food intake, appear to be the main mechanism through which MK-5046 reduces weight when used chronically. In rats, the substance also caused slight increases in blood pressure, heart rate, and body temperature in addition to effectively lowering body weight. These subsequent effects on blood pressure, heart rate, and temperature were only momentary and became less pronounced with continued dosage. The first BRS-3 agonist with features appropriate for usage in larger mammals is MK-5046. Treatment with MK-5046 resulted in statistically significant and long-lasting weight loss in dogs. Initially, there were increases in body temperature and heart rate, but these decreased as the dosage was continued. Our findings support BRS-3 agonism as a novel strategy for treating obesity and show that MK-5046 has antiobesity efficacy in both rats and dogs.
| Targets |
human BRS3 ( IC50 = 28 nM ); mouse BRS3 ( IC50 = 5.4 nM ); rat BRS3 ( IC50 = 1.2 nM ); dog BRS3 ( IC50 = 6.5 nM ); rhesus BRS3 ( IC50 = 50 nM )
The IC50 values of MK-5046 against human, mouse, mouse, dog and macaque BRS3 are 28, 5.4, 1.2, 6.5 and 50 nM respectively [2]. The Ki values of MK-5046 for human, mouse, rat, dog and macaque BRS3 are 3.4, 1.6, 0.6, 9.9 and 2.4 nM respectively[2]. The EC50 values of MK-5046 against human, mouse, monkey, dog and macaque BRS3 are 14, 21, 2.2, 1.6 and 6.9 respectively. MK-5046 inhibits the rabbit calcium channel diltiazem (DLZ) site with an IC50 value of 1.9 μM[2]. |
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| ln Vitro |
The IC50 values of MK-5046 against human, mouse, mouse, dog and macaque BRS3 are 28, 5.4, 1.2, 6.5 and 50 nM respectively [2]. The Ki values of MK-5046 for human, mouse, rat, dog and macaque BRS3 are 3.4, 1.6, 0.6, 9.9 and 2.4 nM respectively[2]. The EC50 values of MK-5046 against human, mouse, monkey, dog and macaque BRS3 are 14, 21, 2.2, 1.6 and 6.9 respectively. MK-5046 inhibits the rabbit calcium channel diltiazem (DLZ) site with an IC50 value of 1.9 μM[2].
MK-5046 exhibited potent binding and functional agonist activity at the human BRS-3 receptor, with an IC₅₀ of 27 ± 13 nM, a Kᵢ of 3.7 ± 0.5 nM, and an EC₅₀ of 25 ± 3 nM (102 ± 6% maximal activation relative to reference peptide). It showed high selectivity (>10,000 nM IC₅₀) over related bombesin family receptors NMBR and GRPR. [2] In a broad off-target screening panel (>100 receptors, ion channels, enzymes), eight off-target activities were identified with IC₅₀ values between 0.5–10 μM, but none were considered significant enough to preclude development. Specific data includes: binding to the human ether-à-go-go-related gene (hERG) potassium channel (Kᵢ > 8 μM), inhibition of the diltiazem (DLZ) site of the rabbit calcium ion channel (IC₅₀ = 1.9 μM), and activation of human pregnane X receptor (hPXR) (EC₅₀ > 25 μM). [2] The compound was evaluated in P-glycoprotein (P-gp) susceptibility and permeability assays, but specific quantitative results for MK-5046 are not provided in the main text. Earlier leads in the series were noted to have high passive permeability. [2] |
| ln Vivo |
MK-5046 (3, 10 and 30 mg/kg; pathway, once) inhibits channel opening and increases resting metabolic rate (MR) in response to diet-induced response (DIO) and diet [1]. 5, 25 and 50 mg/kg; subcutaneous injection once daily for 14 days) significantly reduced body weight and food intake in DIO mice [1]. Animal model: Male C57BL/6N mice, high-fat diet is the diet-induced obesity (DIO) model [1] Dosage: 3, 10 and 30 mg/kg Dosing method: Orally; 3, 10 and 30 mg/kg, once Results: DIO mice dose-dependently suppressed food intake at 2 hours and overnight. But it had no effect on Brs3 knockout mice.
In wild-type (WT) mice, acute administration of MK-5046 caused significant reductions in food intake and an increase in fasting metabolic rate. These effects were absent in BRS-3 knockout (KO) mice, confirming a mechanism-based action. [2] In a subchronic efficacy study in established diet-induced obese (eDIO) mice, continuous subcutaneous infusion of MK-5046 at a dose of 25 mg/kg/day for 14 days resulted in a sustained 8–9% reduction in body weight compared to vehicle-treated controls, with no evidence of tachyphylaxis. [2] |
| Cell Assay |
The functional agonist activity (EC₅₀) of MK-5046 was determined using an aequorin bioluminescence assay measuring agonist-induced intracellular calcium mobilization in HEK293AEQ cells overexpressing the BRS-3 receptor. [2]
Receptor binding assays (IC₅₀, Kᵢ) were performed using membranes from CHO or HEK293 cells overexpressing the indicated receptors (human, mouse, rat, dog, rhesus BRS-3). Binding was competed against reference radioligands. [2] |
| Animal Protocol |
Male C57BL/6N mice with high-fat diet for the diet-induced obese (DIO) model
3, 10 and 30 mg/kg Oral administration; 3, 10 and 30 mg/kg for once The acute pharmacological effects on food intake and metabolic rate were assessed in wild-type and BRS-3 knockout mice. The specific dose, formulation, and route of administration for these acute studies are not detailed. [2] The subchronic body weight lowering efficacy study was conducted in established diet-induced obese (eDIO) mice. MK-5046 was administered via continuous subcutaneous infusion at a dose of 25 mg/kg/day for a duration of 14 days. [2] Pharmacokinetic studies were conducted in mice, rats, dogs, and rhesus monkeys following intravenous (iv) and oral (po) administration. Specific doses included: iv doses of 0.5 or 1 mg/kg, and oral doses of 1 or 2 mg/kg. The formulation details are not provided. [2] |
| ADME/Pharmacokinetics |
The plasma protein binding rate was assessed, and the results showed that the free fraction (Fᵤ) in rat plasma was 1.0%. [2]
After intravenous injection of 1 mg/kg in rats, the pharmacokinetic parameters were: plasma clearance (Clₚ) = 5.6 mL/min/kg, steady-state volume of distribution (Vdₛₛ) = 0.45 L/kg, and half-life (T₁/₂) = 1.4 h. After oral administration of 1 mg/kg, the standardized free oral exposure (po AUCᵤ) = 3.7 µM·h/(mg/kg), and the oral bioavailability (Fᵣᵣₐₗ) = 52%. [2] Pharmacokinetic parameters for other species have also been provided: mice (Clₚ=20 mL/min/kg, T₁/₂=0.7 h, Fᵣᵣₐₗ=64%), dogs (Clₚ=8.8 mL/min/kg, T₁/₂=1.0 h, Fᵣᵣₐₗ=18%), and rhesus monkeys (Clₚ=32 mL/min/kg, T₁/₂=1.1 h, Fᵣᵣₐₗ=9.6%). [2] The metabolic stability of the early lead compound was assessed in rat liver microsomal incubation, and the results showed that oxidative metabolism of the pyridine ring and imidazole substituents was the main clearance pathway, and subsequent modifications (such as those in MK-5046) were designed to reduce this metabolism. Specific microsomal stability data for MK-5046 are not provided. [2] |
| References |
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| Additional Infomation |
MK-5046 is a small molecule agonist that activates the orphan G protein-coupled receptor BRS-3 and has been developed as a potential treatment for obesity. [2] Its weight-loss mechanism is thought to be the activation of centrally expressed BRS-3, thereby reducing food intake and increasing energy expenditure. [2] Compared to previous lead compounds, MK-5046 was selected for further pharmacological studies and clinical trials due to its improved in vitro potency, selectivity, and oral exposure in preclinical animal models. [2]
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| Molecular Formula |
C20H18F6N4O
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|---|---|
| Molecular Weight |
444.37
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| Exact Mass |
444.138
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| Elemental Analysis |
C, 54.06; H, 4.08; F, 25.65; N, 12.61; O, 3.60
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| CAS # |
1022152-70-0
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| Related CAS # |
(R)-MK-5046; 1021736-25-3
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| PubChem CID |
49871766
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| Appearance |
White to light yellow solid powder
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| LogP |
4.473
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
31
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| Complexity |
632
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| Defined Atom Stereocenter Count |
1
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| SMILES |
O[C@](CC1=NC(CC2(C(F)(F)F)CC2)=CN1)(C(F)(F)F)C3=CC=C(N4C=CC=N4)C=C3
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| InChi Key |
UJINBEQCDMOAHM-SFHVURJKSA-N
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| InChi Code |
InChI=1S/C20H18F6N4O/c21-19(22,23)17(6-7-17)10-14-12-27-16(29-14)11-18(31,20(24,25)26)13-2-4-15(5-3-13)30-9-1-8-28-30/h1-5,8-9,12,31H,6-7,10-11H2,(H,27,29)/t18-/m0/s1
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| Chemical Name |
(2S)-1,1,1-trifluoro-2-(4-pyrazol-1-ylphenyl)-3-[5-[[1-(trifluoromethyl)cyclopropyl]methyl]-1H-imidazol-2-yl]propan-2-ol
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| Synonyms |
MK-5046; MK5046; MK 5046
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: ~14.3 mg/mL (~32.2 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1.43 mg/mL (3.22 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 14.3 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 1.43 mg/mL (3.22 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 14.3 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 1.43 mg/mL (3.22 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2504 mL | 11.2519 mL | 22.5038 mL | |
| 5 mM | 0.4501 mL | 2.2504 mL | 4.5008 mL | |
| 10 mM | 0.2250 mL | 1.1252 mL | 2.2504 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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