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| 5mg |
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| 25mg |
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Purity: ≥98%
MK-4256 is a novel, potent and selective SSTR3 (somatostatin subtype receptor 3) antagonist with IC50s of 0.66 nM and 0.36 nM in human and mouse receptor binding assays, respectively. Somatostatin subtype receptor 3 (sstr3) antagonistic therapy has been proposed as a possible treatment for Type 2 diabetes. Because of a dose-dependent prolongation of the QTc (QT interval corrected for heart rate) seen in a conscious cardiovascular (CV) dog model, the development of our first preclinical candidate, MK-4256, was regrettably abandoned.
| Targets |
human SSTR3 ( IC50 = 0.66 nM ); mouse SSTR3 ( IC50 = 0.36 nM )
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| ln Vitro |
MK-4256 has shown selectivity for other SSTR subtypes in in vitro experiments. In human adsorptive binding assays, MK-4256 has an IC50 of >2 μM for SSTR1 and SSTR2. Although SSTR4 and SSTR5 have IC50 values below 1 μM, they are >500-fold selective. MK-4256 was tested in functional antagonist assays against SSTR4 and SSTR5. IC50 value is greater than 5 μM (at least 5000 times selectivity) [1]. -4256 dilution labeled MK-499 binds to hERG channel, IC50=1.74 μM. In functional patch clamp assays, MK-4256 demonstrated 50% amplification of hERG at a concentration of 3.4 μM [2].
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| ln Vivo |
MK-4256 reduces blood glucose excursions in a dose-dependent manner, achieving maximum efficacy at doses as low as 0.03 mg/kg po. MK-4256 exhibits superior SSTR3-mediated glucose-lowering efficacy with minimal low-risk trends in a mouse oGTT model. MK-4256 achieved complete ablation of drift drift (109%) at 1 mg/kg po. MK-4256 reduced drift drift from 0.003 to 10 mg/kg in a dose-dependent manner. MK-4256 At simulated doses of 0.01, 0.1 and 1 mg/kg, MK-4256 reached Cmax of 7, 88 and 493 nM, respectively [1].
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| Animal Protocol |
Mice: In SSTR3 KO mice, the impact of a maximally effective dosage of MK-4256 on blood glucose excursion during an oGTT was examined in order to show that the observed glucose lowering by MK-4256 is SSTR3-dependent. When given to age-matched C57BL/6N male WT mice, MK-4256 (1 mg/kg) and compound A (1 mg/kg; des-F-sitagliptin, a DPP-4 inhibitor included as a positive control) significantly reduce blood glucose excursion by 112 and 91%, respectively.
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| References |
| Molecular Formula |
C27H23FN8O
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|---|---|
| Molecular Weight |
494.522927522659
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| Exact Mass |
494.2
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| Elemental Analysis |
C, 65.58; H, 4.69; F, 3.84; N, 22.66; O, 3.24
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| CAS # |
1104599-69-0
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| Appearance |
Solid powder
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| SMILES |
CC1=NC(=NO1)[C@]2(C3=C(C[C@@H](N2)C4=NC=C(N4)C5=CC=C(C=C5)F)C6=CC=CC=C6N3)C7=CN(N=C7)C
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| InChi Key |
NTIFDLOQPKMIJK-AJTFRIOCSA-N
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| InChi Code |
InChI=1S/C27H23FN8O/c1-15-31-26(35-37-15)27(17-12-30-36(2)14-17)24-20(19-5-3-4-6-21(19)32-24)11-22(34-27)25-29-13-23(33-25)16-7-9-18(28)10-8-16/h3-10,12-14,22,32,34H,11H2,1-2H3,(H,29,33)/t22-,27-/m1/s1
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| Chemical Name |
3-[(1R,3R)-3-[5-(4-fluorophenyl)-1H-imidazol-2-yl]-1-(1-methylpyrazol-4-yl)-2,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]-5-methyl-1,2,4-oxadiazole
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| Synonyms |
MK4256; MK-4256; MK 4256
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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: ≥ 100 mg/mL (~202.2 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 3 mg/mL (6.07 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 30.0 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: ≥ 3 mg/mL (6.07 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 30.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0222 mL | 10.1108 mL | 20.2216 mL | |
| 5 mM | 0.4044 mL | 2.0222 mL | 4.0443 mL | |
| 10 mM | 0.2022 mL | 1.0111 mL | 2.0222 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.
Compound8dose dependently reduces glucose excursion in the mouse oGTT model.ACS Med Chem Lett.2012 May 7;3(6):484-9. |
Compound8has minimal hypoglycemia risk.ACS Med Chem Lett.2012 May 7;3(6):484-9. |
Effects of8and DPP-4 inhibitor compound A (des-F sitagliptin) on oGTT glucose levels in SSTR3 KO and WT mice.ACS Med Chem Lett.2012 May 7;3(6):484-9. |
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