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 IC(50) values of 5.5, 1.0, 11.7, 2.4 and 6.3 microM, respectively. The thiol form (JTP-25203) also inhibited those activities with IC(50) values of 2.8, 0.44, 0.52, 1.3 and 1.1 microM, 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 alpha-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.
Okamoto
Hiroshi
H
Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, 569-1125, Osaka, Japan. hiroshi.okamoto@ims.jti.co.jp
Iwamoto
Yoko
Y
Maki
Mimi
M
Sotani
Tomohiro
T
Yonemori
Fumihiko
F
Wakitani
Korekiyo
K
D000284:Administration, Oral; D000577:Amides; D000818:Animals; D002144:Callithrix; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000097:blood*; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL / Q000097:blood / Q000187:drug effects; D006224:Cricetinae; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004952:Esters; D006023:Glycoproteins; D006801:Humans; D066298:In Vitro Techniques; D008055:Lipids / Q000097:blood*; D008074:Lipoproteins / Q000097:blood / Q000187:drug effects; D008252:Macaca fascicularis; D008297:Male; D011817:Rabbits; D013045:Species Specificity; D013438:Sulfhydryl Compounds / Q000494:pharmacology*
D000577:Amides; C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D004791:Enzyme Inhibitors; D004952:Esters; D006023:Glycoproteins; D008055:Lipids; D008074:Lipoproteins; D013438:Sulfhydryl Compounds; C411602:dalcetrapib