Synthesis and structure-activity relationship of 4-substituted benzoic acids and their inhibitory effect on the biosynthesis of fatty acids and sterols.
The synthesis of 4-[3-(substituted phenyl)-2-oxo-5-oxazolidinyl]methoxybenzoic acids and their inhibitory effects on the biosynthesis of fatty acids and sterols is described. IC50 values in vitro were 10(-6) and 10(-5) M, respectively. Though the in vitro inhibitory activity of all these compounds toward sterol biosynthesis was inferior to that of pravastatin, several compounds had a stronger reducing effect in Sprague-Dawley (SD) rat on both, cholesterol (TC) and triglyceride (TG), than pravastatin and bezafibrate. The potent compounds were present at high concentrations in rat liver. The enantiomers of the potent racemic compounds (4-[3-(4-bromo-2-fluorophenyl)-2-oxo-5-oxazolidinyl]methoxybenzoic acid) were prepared and their activity was examined in vivo and in vitro. In vivo, each enantiomer possessed more activity than the racemic compound. Further, in Watanabe hereditable hyperlipidemic (WHHL) rabbit, optically active (R)-4-[3-(4-bromo-2-fluorophenyl)-2-oxo-5-oxazolidinyl]methoxybenzoic acid also potently reduced the effect of both TC and TG on serum levels, compared with pravastatin and bezafibrate.
Ohno
Tomoyasu
T
Hanno Research Center, Taiho Pharmaceutical Co. Ltd., Hanno, Japan. tom-ohno@taiho.co.jp
Ogawa
Kazuo
K
Yano
Shingo
S
Fukushima
Masakazu
M
Suzuki
Norihiko
N
Asao
Tetsuji
T
D000818:Animals; D001565:Benzoates / Q000138:chemical synthesis* / Q000494:pharmacology*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002784:Cholesterol / Q000096:biosynthesis; D003864:Depression, Chemical; D005227:Fatty Acids / Q000096:biosynthesis*; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013261:Sterols / Q000096:biosynthesis*; D013329:Structure-Activity Relationship; D014280:Triglycerides / Q000097:blood
D001565:Benzoates; D005227:Fatty Acids; D013261:Sterols; D014280:Triglycerides; D002784:Cholesterol