MK-6892 (MK6892) is a novel, potent and selective full agonist for GPR109A, which is a high affinity nicotinic acid receptor. GPR109A is activated with Ki and GTPγS EC50 values of 4 nM and 16 nM on Human GPR109A, respectively. Biaryl cyclohexene carboxylic acids were discovered as full and potent niacin receptor (GPR109A) agonists. In rats and dogs, MK-6892 showed superior therapeutic window over niacin with respect to FFA reduction versus vasodilation, along with good ancillary pharmacology, good PK across species, and exceptionally clean off-target profiles.

Physicochemical Properties

Molecular Formula	C19H22N4O5
Molecular Weight	386.408
Exact Mass	386.159
Elemental Analysis	C, 59.06; H, 5.74; N, 14.50; O, 20.70
CAS #	917910-45-3
PubChem CID	135416394
Appearance	White to off-white solid powder
LogP	3.275
Hydrogen Bond Donor Count	3
Hydrogen Bond Acceptor Count	8
Rotatable Bond Count	6
Heavy Atom Count	28
Complexity	636
Defined Atom Stereocenter Count	0
SMILES	O=C(C1CCCCC=1NC(C(CC1ON=C(C2C=CC(O)=CN=2)N=1)(C)C)=O)O
InChi Key	CJHXBFSJXDUJHP-UHFFFAOYSA-N
InChi Code	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)
Chemical Name	2-[[3-[3-(5-hydroxypyridin-2-yl)-1,2,4-oxadiazol-5-yl]-2,2-dimethylpropanoyl]amino]cyclohexene-1-carboxylic acid
Synonyms	MK-6892; MK 6892; MK6892
HS Tariff Code	2934.99.9001
Storage	Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

Targets	GPR109A ( Ki = 4 nM ); GPR109A ( EC50 = 16 nM )
ln Vitro	MK-6892 stimulates GPR109A to internalize powerfully in U2OS β-arrestin2-RrGFP cells.In the calcium mobilization assay, MK-6892 exhibits an EC50 value of 74 nM[2].
ln Vivo	MK-6892 is given orally to mice bearing the same genetic background (C57Bl/6) that are WT or nicotinic acid (NA) receptor null. The blood levels of MK-6892 at 15 minutes 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. This is after feeding WT or NA receptor null mice 100 mg/kg of MK-6892 for 15 minutes. MK-6892 efficiently reduces plasma FFA in WT animals but not in NA receptor null animals, suggesting that MK-6892's FFA reduction is dependent on NA receptors. MK-6892 has been chosen for the research due to its favorable PK and activity profiles in these two species (EC50= 1.3 μM for the dog NA receptor and 4.6 μM for the rat NA receptor in the GTPηS assay). Although MK-6892 exhibits significantly less activity in rat and dog models compared to human models, it still demonstrates good activity in reducing FFA in these models[1].
References	[1]. 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. [2]. 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.

Solubility Data

Solubility (In Vitro)

DMSO: ~50 mg/mL (~129.4 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.47 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (6.47 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 2.5 mg/mL (6.47 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.5879 mL	12.9396 mL	25.8792 mL
	5 mM	0.5176 mL	2.5879 mL	5.1758 mL
	10 mM	0.2588 mL	1.2940 mL	2.5879 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.