Novel calcium antagonists with both calcium overload inhibition and antioxidant activity. 2. Structure-activity relationships of thiazolidinone derivatives

CP-060 (1), 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-[3,4-(methylenedioxy)phenoxy]ethyl]amino]propyl]-1,3-thiazolidin-4-one, is a novel type of Ca2+ antagonist possessing both Ca2+ overload inhibition and antioxidant activity. The structure-activity relationships for this series of compounds were studied by synthesizing the analogues and evaluating these three kinds of activity. Ca2+ antagonistic activity was largely determined by the lipophilicity of the phenyl group at the 2-position and the length of the alkyl chains. As for-the antioxidant activity, it was demonstrated that the phenolic hydroxyl group is an essential structural element. Compounds with potent activity were! evaluated for their effect on the coronary blood flow in vivo. Among these compounds, compound 1 was shown to be the most potent. Furthermore, the enantiomers of 1 were resolved by high-performance liquid chromatography with a chiral column. Compound (-)-1 showed about 10 times higher Ca2+ antagonistic activity than (+)-1, though both enarrtiomers had similar potency in Ca2+ overload inhibition and antioxidant activity. An X-ray crystal structure determination of (-)-1 hydrogen fumarate identified (-)-1 as having S configuration at the 2-position.