title: Synthesis and structure-activity relationship of 4-substituted benzoic acids and their inhibitory effect on the biosynthesis of fatty acids and sterols.
abstract: 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.
authors.affiliation: Hanno Research Center, Taiho Pharmaceutical Co. Ltd., Hanno, Japan. tom-ohno@taiho.co.jp
authors.forename: Tomoyasu
authors.initials: T
authors.lastname: Ohno
authors.forename: Kazuo
authors.initials: K
authors.lastname: Ogawa
authors.forename: Shingo
authors.initials: S
authors.lastname: Yano
authors.forename: Masakazu
authors.initials: M
authors.lastname: Fukushima
authors.forename: Norihiko
authors.initials: N
authors.lastname: Suzuki
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Asao
mesh_terms: 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
chemical_list: D001565:Benzoates; D005227:Fatty Acids; D013261:Sterols; D014280:Triglycerides; D002784:Cholesterol