Name | MK-4256 |
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Synonyms |
(1R,3R)-3-[4-(4-Fluorophenyl)-1H-imidazol-2-yl]-1-(5-methyl-1,2,4-oxadiazol-3-yl)-1-(1-methyl-1H-pyrazol-4-yl)-2,3,4,9-tetrahydro-1H-β-carboline
1H-Pyrido[3,4-b]indole, 3-[4-(4-fluorophenyl)-1H-imidazol-2-yl]-2,3,4,9-tetrahydro-1-(5-methyl-1,2,4-oxadiazol-3-yl)-1-(1-methyl-1H-pyrazol-4-yl)-, (1R,3R)- |
Description | MK-4256 is a potent and selective SSTR3 antagonist with IC50s of 0.66 nM and 0.36 nM in human and mouse receptor binding assays, respectively. |
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Related Catalog | |
Target |
IC50: 0.66 nM (human SSTR3), 0.36 nM (mouse SSTR3)[1] |
In Vitro | MK-4256 has excellent selectivity against other SSTR subtypes based on in vitro assays. In human receptor binding assays, MK-4256 has IC50s >2 μM for SSTR1 and SSTR2. Although the binding IC50 values on SSTR4 and SSTR5 are below 1 μM, there is still >500-fold selectivity. MK-4256 is tested in functional antagonist assays against SSTR4 and SSTR5. The IC50 values are greater than 5 μM (at least 5000-fold selectivity)[1]. MK-4256 inhibits radiolabeled MK-499 binding of the hERG channel with an IC50=1.74 μM. In a functional patch clamp assay, MK-4256 exhibits 50% blockade of hERG at 3.4 μM concentration[2]. |
In Vivo | MK-4256 reduces glucose excursion in a dose-dependent fashion with maximal efficacy achieves at doses as low as 0.03 mg/kg po. MK-4256 demonstrates exceptional SSTR3-mediated glucose-lowering efficacy in the mouse oGTT model with minimal hypoglycemia risk. MK-4256 achieves complete ablation of glucose excursion (109%) at 1 mg/kg po. MK-4256 reduces the glucose excursion from 0.003 to 10 mg/kg in a dose-dependent manner. The plasma Cmax of MK-4256 is determined from parallel mouse PK studies. At 0.01, 0.1, and 1 mg/kg oral dose, MK-4256 achieves Cmax of 7, 88, and 493 nM, respectivley[1]. |
Animal Admin | Mice[1] To demonstrate that the observed glucose lowering by MK-4256 is SSTR3-dependent, the effect of a maximally efficacious dosage of MK-4256 on blood glucose excursion during an oGTT was investigated in SSTR3 KO mice. Administration of MK-4256 (1 mg/kg) and compound A (1 mg/kg; des-F-sitagliptin, a DPP-4 inhibitor included as a positive control) to age-matched C57BL/6N male WT mice significantly inhibits blood glucose excursion by 112 and 91%, respectively. |
References |
Density | 1.5±0.1 g/cm3 |
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Boiling Point | 826.7±75.0 °C at 760 mmHg |
Molecular Formula | C27H23FN8O |
Molecular Weight | 494.523 |
Flash Point | 453.8±37.1 °C |
Exact Mass | 494.197876 |
LogP | 2.41 |
Vapour Pressure | 0.0±3.0 mmHg at 25°C |
Index of Refraction | 1.780 |
Storage condition | 2-8℃ |