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Synthesis and Structure‐Activity Relationship of 4‐Substituted Benzoic Acids and their Inhibitory Effect on the Biosynthesis of Fatty Acids and Sterols
Author(s) -
Ohno Tomoyasu,
Ogawa Kazuo,
Yano Shingo,
Fukushima Masakazu,
Suzuki Norihiko,
Asao Tetsuji
Publication year - 2005
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.200400920
Subject(s) - bezafibrate , chemistry , pravastatin , enantiomer , biosynthesis , in vivo , stereochemistry , in vitro , triglyceride , biochemistry , cholesterol , enzyme , biology , microbiology and biotechnology
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. IC 50 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.