Dalcetrapib (JTT-705)

389, 59

Syrian hamsters

Dalcetrapib has enered in a Phase III clinical trial in the treatment of cardiovascular disease, dyslipidemia, peripheral arterial disease (PAD).

100 mg/kg

0.2 uM [1], 0.2 uM [1], 0.2 uM [1], 0.2 uM [1], 0.2 uM [1], 0.2 uM [1]

Treatment with Dalcetrapib leads to significant increases in HDL-C levels. In hamsters injected with [3H]cholesterol-labeled autologous macrophages Dalcetrapib significantly increases fecal elimination of both [3H]neutral sterols and [3H]bile acids. Dalcetrapib increases plasma HDL-[3H]cholesterol. [1] Dalcetrapib has 95% inhibition of CETP activity in male Japanese white rabbits at an oral dose of 30 mg/kg. Dalcetrapib increases the plasma HDL cholesterol level by 27% and 54%, respectively, when given at oral doses of 30 mg/kg or 100 mg/kg once a day for 3 days to male Japanese white rabbits. [2] Treatment with Dalcetrapib markedly increases serum levels of HDL-C. The ratio of HDL2-C to HDL3-C is significantly higher in Dalcetrapib–treated rabbits than in control rabbits at 5 and 7 months, indicating that the inhibition of CETP activity by Dalcetrapib changes the distribution of HDL subfractions and preferentially increases HDL2-C levels. Dalcetrapib treatment increases serum paraoxonase activity and HDL-sociated platelet-activating factor acetylhydrolase activity, but decreases the plasma lysophosphatidylcholine concentration. [4]

Inhibition of rhCETP and C13S CETP-mediated transfer of CE from HDL to LDL, The inhibitory potency (IC50) of Dalcetrapib to decrease CE transfer from HDL to LDL by rhCETP and C13S CETP is measured using a scintillation proximity assay kit. Briefly, [3H]CE-labeled HDL donor particles are incubated in the presence of purified CETP proteins (final concentration 0.5 ug/mL) and biotinylated LDL acceptor particles for 3 hours at 37 C. Subsequently, streptavidin-coupled polyvinyltoluene beads containing liquid scintillation cocktail binding selectively to biotinylated LDL are added, and the amount of [3H]CE molecules transferred to LDL is measured by beta counting.

DMSO 78 mg/mL, Water <1 mg/mL, Ethanol 78 mg/mL

S-2-(1-(2-ethylbutyl)cyclohexanecarboxamido)phenyl 2-methylpropanethioate