| Size | Price | Stock | Qty |
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Purity: ≥98%
MK-6892 (MK6892) is a novel, potent and selective full agonist for GPR109A, which is a high affinity nicotinic acid receptor. GPR109A is activated with Ki and GTPγS EC50 values of 4 nM and 16 nM on Human GPR109A, respectively. Biaryl cyclohexene carboxylic acids were discovered as full and potent niacin receptor (GPR109A) agonists. In rats and dogs, MK-6892 showed superior therapeutic window over niacin with respect to FFA reduction versus vasodilation, along with good ancillary pharmacology, good PK across species, and exceptionally clean off-target profiles.
| Targets |
GPR109A ( Ki = 4 nM ); GPR109A ( EC50 = 16 nM )
MK-6892 stimulates GPR109A to internalize powerfully in U2OS β-arrestin2-RrGFP cells.In the calcium mobilization assay, MK-6892 exhibits an EC50 value of 74 nM[2]. |
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| ln Vitro |
MK-6892 stimulates GPR109A to internalize powerfully in U2OS β-arrestin2-RrGFP cells.In the calcium mobilization assay, MK-6892 exhibits an EC50 value of 74 nM[2].
In a competitive binding assay using membranes from CHO cells expressing recombinant human GPR109A, MK-6892 displaced tritiated niacin with a Ki of 4 nM. In the presence of 4% human serum, the Ki shifted to 595 nM. In a guanine nucleotide exchange (GTPγS) assay using the same membranes, MK-6892 acted as a full agonist with an EC50 of 16 nM, achieving the same maximal response as niacin. The compound showed no activity against the closely related receptors GPR109B and GPR81 in counter-screening assays. It was also tested in a panel of 166 different biological target counter-screening assays and showed no significant off-target activity (IC50 > 10 μM). In cytochrome P450 inhibition assays, MK-6892 had IC50 values > 100 μM for CYP2C8, 2D6, and 3A4, and an IC50 of 39 μM for CYP2C9. [1] |
| ln Vivo |
MK-6892 is given orally to mice bearing the same genetic background (C57Bl/6) that are WT or nicotinic acid (NA) receptor null. The blood levels of MK-6892 at 15 minutes are 229 μM (~950-fold greater than the in vitro EC50 determined in mouse NA receptor GTPγS assay, which is 240 nM) in WT mice and 148 μM (~620-fold greater than the in vitro EC50) in NA receptor null mice. This is after feeding WT or NA receptor null mice 100 mg/kg of MK-6892 for 15 minutes. MK-6892 efficiently reduces plasma FFA in WT animals but not in NA receptor null animals, suggesting that MK-6892's FFA reduction is dependent on NA receptors. MK-6892 has been chosen for the research due to its favorable PK and activity profiles in these two species (EC50= 1.3 μM for the dog NA receptor and 4.6 μM for the rat NA receptor in the GTPηS assay). Although MK-6892 exhibits significantly less activity in rat and dog models compared to human models, it still demonstrates good activity in reducing FFA in these models[1].
Oral administration of MK-6892 (100 mg/kg) to wild-type (WT) C57Bl/6 mice effectively suppressed plasma free fatty acid (FFA) levels 15 minutes post-dose. This effect was absent in GPR109A (NA receptor) null mice, confirming the effect was receptor-dependent. In conscious rats, oral MK-6892 (1-100 mg/kg) produced a dose-dependent reduction in plasma FFA levels, with a maximal suppression of ~85%. The magnitude and duration of FFA reduction were comparable to niacin. In anesthetized rats, subcutaneous administration of MK-6892 at a high dose (100 mg/kg) induced vasodilation (flushing) in only 5 out of 10 animals, and the average magnitude was considerably less than that induced by niacin at doses ≥3 mg/kg. In fasted dogs, oral MK-6892 (1-100 mg/kg) demonstrated dose-dependent antilipolytic activity, resulting in 85-90% maximal FFA suppression with a duration of action >4 hours. Flushing was observed in only 1 out of 4 dogs at the highest dose (100 mg/kg), and it was relatively mild. [1] |
| Enzyme Assay |
The functional activity of MK-6892 on GPR109A was determined using a guanine nucleotide exchange (GTPγS) assay. Membranes were prepared from Chinese hamster ovary (CHO) cells stably expressing recombinant human, mouse, rat, or dog GPR109A. Agonist-stimulated binding of the non-hydrolyzable GTP analog [35S]GTPγS to Gαi proteins was measured. The EC50 value represents the concentration of agonist required to produce half-maximal stimulation. [1]
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| Cell Assay |
Calcium Mobilization Assay: CHO-K1/Gα16 cells stably transfected with GPR109A were seeded in 96-well plates. After serum starvation, cells were loaded with a fluorescent calcium indicator dye. Fluorescence emission was measured after compound stimulation using a plate reader. Agonist activity was calculated as a percentage relative to the response elicited by 10 μM niacin. [2]
β-Arrestin Recruitment Assay: Tango™ GPR109A-bla U2OS cells were stimulated with compounds for 5 hours. A β-lactamase substrate (CCF4-AM) was then loaded, and the fluorescence emission ratio (blue/green) was measured. An increase in the ratio indicates β-arrestin recruitment and receptor activation. [2] Receptor Internalization Assay (High-Content Imaging): U2OS cells stably co-expressing GPR109A and β-arrestin2 fused to red-shifted green fluorescent protein (RrGFP) were seeded in glass-bottom plates. After nuclear staining and compound treatment (1 μM) for varying times (0-60 min), cells were fixed. The intracellular redistribution of the fluorescent β-arrestin2 signal (formation of cytoplasmic pits) was analyzed using a high-content screening reader to assess receptor internalization. [2] |
| Animal Protocol |
For pharmacodynamic (FFA reduction) studies in mice, MK-6892 was administered orally at 100 mg/kg to fed wild-type or GPR109A null mice, and blood was collected 15 minutes post-dose for plasma FFA measurement.
For FFA reduction studies in conscious rats, MK-6892 was dissolved in an unspecified vehicle and administered orally at doses ranging from 1 to 100 mg/kg. Blood samples were collected at various time points over 4 hours to measure plasma FFA levels. For vasodilation (flushing) studies in anesthetized rats, MK-6892 was administered subcutaneously at doses up to 100 mg/kg. Flushing was monitored on the ears using laser Doppler flowmetry. For threshold vasodilation studies in rats, MK-6892 was administered intraperitoneally at 100 mg/kg, and plasma drug levels were measured 15 minutes post-dose (corresponding to Tmax). For studies in conscious dogs, MK-6892 was administered orally at doses ranging from 1 to 100 mg/kg to fasted animals. Both plasma FFA levels and signs of flushing (assessed by spectrocolorimetry of the ear and observation of vocal/physical agitation) were monitored. [1] |
| ADME/Pharmacokinetics |
MK-6892 exhibited small volume of distribution, low clearance, and good oral bioavailability in various species. In rats, its half-life was 4.3 hours, and its clearance was 0.4 L/h/kg. In dogs and mice, its bioavailability was excellent; in rats and rhesus monkeys, its bioavailability was moderate (specific values not provided). The correlation between drug exposure and pharmacodynamic effects (reduction of free fatty acids) was analyzed using plasma drug concentration-time curves. [1]
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| Toxicity/Toxicokinetics |
MK-6892 showed excellent off-target effects in the reverse screening test. In auxiliary pharmacology studies, no preliminary safety issues were observed in central nervous system (mouse), cardiovascular system (dog), gastrointestinal motility system, kidney and respiratory system (dog) models. The presence of the hydroxypyridine group did not introduce any in vivo or in vitro covalent binding issues, thus alleviating concerns about bioactivation. [1]
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| References |
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| Additional Infomation |
MK-6892 (2-(3-{[3-(5-hydroxypyridin-2-yl)-1,2,4-oxadiazol-5-yl]-2,2-dimethylpropionyl}amino)cyclohexyl-1-en-1-carboxylic acid) is a biarylcyclohexenic acid that has been found to be a potent, selective, and complete agonist of the high-affinity niacin receptor GPR109A. Its primary mechanism of action is the activation of GPR109A on adipocytes, thereby inhibiting triglyceride hydrolysis and reducing plasma free fatty acid (FFA) levels, which is associated with beneficial lipid regulation effects (e.g., increasing high-density lipoprotein cholesterol and decreasing triglycerides). A key finding is that its therapeutic index (TI) is superior to niacin in both mouse and canine models. TI is calculated based on the difference between the plasma concentration (or dose, EC50) required to achieve the half-maximum reduction in FFA and the threshold concentration (or dose) required to induce vasodilation (flushing). In rats, the estimated TI (threshold vasodilatory concentration/EC50 with reduced FFA) for MK-6892 was 11.9, while the TI for niacin was 0.54. In dogs, the TI (threshold vasodilatory dose/maximum FFA inhibitor dose) for MK-6892 was 10, while the TI for niacin was 0.5. Based on plasma concentrations, the canine therapeutic index (TI) for MK-6892 was 11.0, while that for niacin was 5.4. MK-6892 was selected as a preclinical candidate for further evaluation due to its superior receptor activity, pharmacokinetic characteristics, good off-target selectivity, good adjunctive pharmacological properties, and a therapeutic window superior to that of niacin. [1]
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| Molecular Formula |
C19H22N4O5
|
|---|---|
| Molecular Weight |
386.408
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| Exact Mass |
386.159
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| Elemental Analysis |
C, 59.06; H, 5.74; N, 14.50; O, 20.70
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| CAS # |
917910-45-3
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| PubChem CID |
135416394
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| Appearance |
White to off-white solid powder
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| LogP |
3.275
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
28
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| Complexity |
636
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(C1CCCCC=1NC(C(CC1ON=C(C2C=CC(O)=CN=2)N=1)(C)C)=O)O
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| InChi Key |
CJHXBFSJXDUJHP-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C19H22N4O5/c1-19(2,18(27)21-13-6-4-3-5-12(13)17(25)26)9-15-22-16(23-28-15)14-8-7-11(24)10-20-14/h7-8,10,24H,3-6,9H2,1-2H3,(H,21,27)(H,25,26)
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| Chemical Name |
2-[[3-[3-(5-hydroxypyridin-2-yl)-1,2,4-oxadiazol-5-yl]-2,2-dimethylpropanoyl]amino]cyclohexene-1-carboxylic acid
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| Synonyms |
MK-6892; MK 6892; MK6892
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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: ~50 mg/mL (~129.4 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.47 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 25.0 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: ≥ 2.5 mg/mL (6.47 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 25.0 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: ≥ 2.5 mg/mL (6.47 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 | 2.5879 mL | 12.9396 mL | 25.8792 mL | |
| 5 mM | 0.5176 mL | 2.5879 mL | 5.1758 mL | |
| 10 mM | 0.2588 mL | 1.2940 mL | 2.5879 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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