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 nov el type of Ca2+ antagonist possessing both Ca2+ overload inhibition and ant ioxidant activity. The structure-activity relationships for this series of compounds were studied by synthesizing the analogues and evaluating these t hree kinds of activity. Ca2+ antagonistic activity was largely determined b y 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 tha t the phenolic hydroxyl group is an essential structural element. Compounds with potent activity were! evaluated for their effect on the coronary bloo d 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 enarrtiome rs had similar potency in Ca2+ overload inhibition and antioxidant activity . An X-ray crystal structure determination of (-)-1 hydrogen fumarate ident ified (-)-1 as having S configuration at the 2-position.