MK-6892

• CAT Number: I005473
• CAS Number: 917910-45-3
• Molecular Formula: C19H22N4O5
• Molecular Weight: 386.40
• Purity: ≥95%
• Synonyms: 2-[[3-[3-(5-hydroxypyridin-2-yl)-1,2,4-oxadiazol-5-yl]-2,2-dimethylpropanoyl]amino]cyclohexene-1-carboxylic acid
• InChI: InChI=1S/C19H22N4O5/c1-19(2,18(27)21-13-6-4-3-5-12(13)17(25)26)9-15-22-16(23-28-15)14-8-7-11(24)10-20-14/h7-8,10,24H,3-6,9H2,1-2H3,(H,21,27)(H,25,26)
• InChIKey: CJHXBFSJXDUJHP-UHFFFAOYSA-N
• SMILES: CC(C)(CC1=NC(=NO1)C2=NC=C(C=C2)O)C(=O)NC3=C(CCCC3)C(=O)O

MK-6892 is a potent, selective, and full agonist for the high affinity nicotinic acid (NA) receptor GPR109A. Ki and GTPγS EC50 of MK-6892 on the Human GPR109A is 4 nM and 16 nM, respectively.
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 EC50 determined 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].

Reference

[1]. Shen HC, et al. Discovery of a biaryl cyclohexene carboxylic acid (MK-6892): a potent and selective high affinity niacin receptor full agonist with reduced flushing profiles in animals as a preclinical candidate. J Med Chem. 2010 Mar 25;53(6):2666-70.
 [Content Brief]

[2]. Kim HY, et al. Discovery of 4-(phenyl)thio-1H-pyrazole derivatives as agonists of GPR109A, a high affinity niacin receptor. Arch Pharm Res. 2015 Jun;38(6):1019-32.
 [Content Brief]