Effect of JTT-705 on cholesteryl ester transfer protein and plasma lipid levels in normolipidemic animals

This study evaluated JTT-705, S-[2-([[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino)phenyl]2-methylpropanethioate, as a cholesteryl ester transfer protein (CETP) inhibitor in several animal species. In vitro, JTT-705 inhibited plasma CETP activities of humans, rabbits, hamsters, cynomolgus monkeys and marmosets with IC50 values of 5.5, 1.0, 11.7, 2.4 and 6.3 muM, respectively. The thiol form (JTP-25203) also inhibited those activities with IC50 values of 2.8, 0.44, 0.52, 1.3 and 1.1 muM, respectively. Following oral administration to normolipidemic animals (rabbits, hamsters and marmosets), JTT-705 reduced plasma CETP activity, increased high density lipoprotein cholesterol (HDL-cholesterol), and decreased the ratio of non-HDL-cholesterol to HDL-cholesterol (atherogenic index) in all species. In marmosets, JTT-705 increased slow a-migrating lipoprotein (apolipoprotein E-rich HDL) in agarose gel electrophoresis, indicating that HDL metabolism in JTT-705-treated marmosets is similar to that in CETP-deficient humans. These results indicate that JTT-705 can be expected to inhibit plasma CETP activity and improve plasma lipoprotein profiles in a wide range of animal species, including humans. (C) 2003 Elsevier Science B.V. All rights reserved.