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-on e, is a novel type of Ca(2+) antagonist possessing both Ca(2+) 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. Ca(2+) 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 Ca(2+) antagonistic activity than (+)-1, though both enantiomers had similar potency in Ca(2+) 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.
Kato
T
T
Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Company, Ltd., 135, 1-Chome Komakado, Gotemba City, Shizuoka 412-8513, Japan.
Ozaki
T
T
Tamura
K
K
Suzuki
Y
Y
Akima
M
M
Ohi
N
N
D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000037:antagonists & inhibitors*; D015220:Calcium Channels / Q000378:metabolism; D020746:Calcium Channels, L-Type; D002851:Chromatography, High Pressure Liquid; D003326:Coronary Circulation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004285:Dogs; D066298:In Vitro Techniques; D015227:Lipid Peroxidation / Q000187:drug effects; D008077:Lipoproteins, LDL / Q000737:chemistry; D008084:Lipoxygenase / Q000737:chemistry; D008297:Male; D008958:Models, Molecular; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D010636:Phenols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013025:Glycine max / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D053778:Thiazolidines
D000975:Antioxidants; C115426:CP 060; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D008077:Lipoproteins, LDL; D010636:Phenols; D013844:Thiazoles; D053778:Thiazolidines; D008084:Lipoxygenase; D002118:Calcium