A potent and selective high affinity niacin receptor (GPR109A) full agonist with Ki of 4.0 nM, EC50 of 16 nM in GTPγS assay.
Description :
A potent and selective high affinity niacin receptor (GPR109A) full agonist with Ki of 4.0 nM, EC50 of 16 nM in GTPγS assay; has no activity on closely related GPCRs GPR109B and GPR81; displays good PK across species, remarkably clean off-target profiles, and superior therapeutic window over niacin regarding the FFA reduction versus vasodilation in rats and dogs.
MK-6892 evokes a potent internalization of GPR109A in U2OS β-arrestin2-RrGFP cells.MK-6892 shows an EC50 value of 74 nM on calcium mobilization assay[2].
MK-6892 is orally administered to WT or nicotinic acid (NA) receptor null mice on the same C57Bl/6 genetic background. After 15 min of 100 mg/kg dosing of MK-6892 to fed WT or NA receptor null mice, the blood levels of MK-6892 at 15 min are 229 μM (~950-fold greater than the in vitro EC50determined 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. MK-6892 effectively suppresses plasma FFA in the WT but not in the NA receptor null animals, indicating that the FFA reduction of MK-6892 is NA receptor-dependent. MK-6892 is selected for the studies because of its good PK and activity profiles in these two species (EC50=4.6 μM in the GTPγS assay for the rat NA receptor and 1.3 μM in the GTPγS assay for the dog NA receptor). Despite the significant weaker activity of MK-6892 in rat and dog with respect to that in human, MK-6892 shows good activity in reducing FFA in rat and dog models[1].