bis(2-(Acylamino)phenyl) disulfides, 2-(acylamino)benzenethiols, and S-(2-(acylamino)phenyl) alkanethioates as novel inhibitors of cholesteryl ester transfer protein.
A series of bis(2-(acylamino)phenyl) disulfides, 2-(acylamino)benzenethiols, S-(2-(acylamino)phenyl) alkanethioates, and related compounds were synthesized, and their inhibitory effect on cholesteryl ester transfer protein activity in human plasma was evaluated. This study elucidated the structural requirements for inhibitory activity and determined that the optimum compound was S-(2-((1-(2-ethylbutyl)cyclohexane)carbonylamino)phenyl) 2-methylpropanethioate (27) (JTT-705). This compound achieved 50% inhibition of CETP activity in human plasma at a concentration of 9 microM and 95% inhibition of CETP activity in male Japanese white rabbits at an oral dose of 30 mg/kg. It increased the plasma HDL cholesterol level by 27% and 54%, respectively, when given at oral doses of 30 or 100 mg/kg once a day for 3 days to male Japanese white rabbits.
Shinkai
H
H
Central Pharmaceutical Research Institute, JT Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan. hisashi.shinkai@ims.jti.co.jp
Maeda
K
K
Yamasaki
T
T
Okamoto
H
H
Uchida
I
I
D000284:Administration, Oral; D000577:Amides; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000097:blood / Q000737:chemistry; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL / Q000097:blood; D003545:Cysteine / Q000737:chemistry; D004220:Disulfides / Q000737:chemistry; D004952:Esters; D006023:Glycoproteins; D006801:Humans; D008297:Male; D011817:Rabbits; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000577:Amides; C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D004220:Disulfides; D004952:Esters; D006023:Glycoproteins; D013438:Sulfhydryl Compounds; C411602:dalcetrapib; D003545:Cysteine