MK-4256 is an effective and selective SSTR3 antagonist (IC50s: 0.66 nM and 0.36 nM in human and mouse receptor binding assays, respectively).

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

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 (IC50=1.74 μM). MK-4256 has excellent selectivity against other SSTR subtypes based on in vitro assays and it also has IC50s >2 μM for SSTR1 and SSTR2, in human receptor binding assays. Although the binding IC50 values on SSTR4 and SSTR5 are below 1 μM, there is still >500-fold selectivity. MK-4256 exhibits 50% blockade of hERG at 3.4 μM concentration, in a functional patch-clamp assay[2].

MK-4256 decreases the glucose excursion from 0.003 to 10 mg/kg in a dose-dependent manner. MK-4256 decreases glucose excursion in a dose-dependent fashion with maximal efficacy achieves at doses of MK-4256 (0.03 mg/kg; p.o.) demonstrates exceptional SSTR3-mediated glucose-lowering efficacy in the mouse oGTT model with minimal hypoglycemia risk. MK-4256 (1 mg/kg; p.o.) achieves complete ablation of glucose excursion (109%). The plasma Cmax of MK-4256 is determined from parallel mouse PK studies. MK-4256 achieves Cmax of 7, 88, and 493 nM, respectively, at 0.01, 0.1, and 1 mg/kg oral dose [1].