Description

Metabolic Disease

Description

A 922500 is a DGAT-1 inhibitor for human and mouse DGAT-1 with IC50 of 7 nM and 24 nM, respectively.

Targets

IC₅₀

In Vitro

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

In Vivo

Zucker fatty rats and diet-induced dyslipidemic hamsters are dosed orally with A 922500 (0.03, 0.3, and 3 mg/kg) for 14 days. Serum triglycerides ae significantly reduced by the 3 mg/kg dose of A 922500 in both the Zucker fatty rat (39%) and hyperlipidemic hamster (53%). These serum triglyceride changes are accompanied by significant reductions in free fatty acid levels by 32% in the Zucker fatty rat and 55% in the hyperlipidemic hamster. In addition, high-density lipoprotein-cholesterol is significantly increases (25%) in the Zucker fatty rat by A 922500 administered at 3 mg/kg. ^[1] A 922500 confers weight loss and a reduction in liver triglycerides when dosed chronically in DIO mice and depletes serum triglycerides following a lipid challenge in a dose-dependent manner, thus, reproducing major phenotypical characteristics of DGAT-1(-/-) mice. ^[2] A 922500 (0.03, 0.3 and 3 mg/kg, p.o.) dose-dependently attenuates the maximal postprandial rise in serum triglyceride concentrations. ^[3]

Clinical Trials

Features

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

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 μM of enzyme substrate (didecanoyl glycerol) and 7.5 μM radiolabeled acyl-CoA substrate. [1- ¹⁴ C]decanoyl-CoA) is added to each well of a phospholipid FlashPlate. A small aliquot of membrane (1 μg/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 μL) 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 μM, 0.001 μM, 0.01 μM, 0.1 μM, 1.0 μM, 10.0 μM) 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%.

Animal Models

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

Formulation

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

Doses

0.03, 0.3, and 3 mg/kg

Administration

Oral gavage