A922500

428, 48

Thirteen-week-old male Golden Syrian hamsters with hyperlipidemia, Ten-week-old Male Zucker fatty rats

Polyethylene glycol/hydroxypropyl-beta-cyclodextrin (10% w/v)

A 922500 inhibits the phylogenetic family members acyl coenzyme A cholesterol acyltransferase-1 and -2 with IC50 of 296 uM. [1] A 922500 potently inhibits huDGAT-1 and mseDGAT-1. [2]

[2], In vitro DGAT-1 activity inhibition assay, DGAT-1 activity is determined as follows: Assay buffer [20 mM HEPES (pH 7.5), 2 mM MgCl2, 0.04% BSA] containing 50 uM of enzyme substrate (didecanoyl glycerol) and 7.5 uM radiolabeled acyl-CoA substrate. [1- 14 C]decanoyl-CoA) is added to each well of a phospholipid FlashPlate. A small aliquot of membrane (1 ug/well) is added to start the reaction, which is allowed to proceed for 60 minutes. The reaction is terminated upon the addition of an equal volume (100 uL) of isopropanol. The plates are sealed, incubated overnight and counted the next morning on a TopCount Scintillation Plate Reader. DGAT-1 catalyzes the transfer of the radiolabel-led decanoyl group onto the sn-3 position of didecanoyl glycerol. The resultant radiolabeled tridecanoyl glycerol (tricaprin) preferentially binds to the hydrophobic coating on the phospholipid FlashPlate. The proximity of the S15 radiolabeled product to the solid scintillant incorporated into the bottom of the FlashPlate induces fluor release from the scintillant, which is measured in the TopCount Plate Reader. Various concentrations (e.g. 0.0001 uM, 0.001 uM, 0.01 uM, 0.1 uM, 1.0 uM, 10.0 uM) of A 922500 are added to individual wells prior to the addition of membranes. The potency of DGAT-1 inhibition for the A 922500 is determined by calculating the IC50 values defined as the inhibitor concentration from the sigmoidal dose response curve at which the enzyme activity is inhibited 50%.

A922500 (DGAT-1 Inhibitor 4a) is an inhibitor for human and mouse DGAT-1 with IC50 of 7 nM and 24 nM, respectively, good selectivity over related acyltransferases, hERG, and a panel of anti-targets.

A 922500 is a potent, selective, and orally bioavailable DGAT-1 inhibitor.