IC50: 0.66 nM (human SSTR3), 0.36 nM (mouse SSTR3)

MK-4256 has excellent selectivity against other SSTR subtypes based on in vitro assays. In human receptor binding assays, MK-4256 has IC ₅₀ s >2 μM for SSTR1 and SSTR2. Although the binding IC ₅₀ 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 IC ₅₀ values are greater than 5 μM (at least 5000-fold selectivity). MK-4256 inhibits radiolabeled MK-499 binding of the hERG channel with an IC ₅₀ =1.74 μM. In a functional patch clamp assay, MK-4256 exhibits 50% blockade of hERG at 3.4 μM concentration.

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 C _max of MK-4256 is determined from parallel mouse PK studies. At 0.01, 0.1, and 1 mg/kg oral dose, MK-4256 achieves C _max of 7, 88, and 493 nM, respectivley.