Design and Synthesis of 4,6-Di-tert-butyl-2,3-dihydro-5-benzofuranols as a Novel Series of Antiatherogenic Antioxidants

Antioxidants have been considered as potential antiatherogenic agents by inhibiting oxidation of low-density lipoprotein (LDL), albeit vitamin E, a natural antioxidant, has failed to show reduction on atherosclerosis in clinical trials. We have rationally designed and synthesized a novel series of a...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2003-07, Vol.46 (14), p.3083-3093
Main Authors: Tamura, Kunio, Kato, Yoshiaki, Ishikawa, Akira, Kato, Yasuharu, Himori, Motomu, Yoshida, Mitsutaka, Takashima, Yoshiaki, Suzuki, Tsukasa, Kawabe, Yoshiki, Cynshi, Osamu, Kodama, Tatsuhiko, Niki, Etsuo, Shimizu, Makoto
Format: Article
Language:English
Subjects:
alpha-Tocopherol - pharmacology
Animals
Antioxidants - chemical synthesis
Antioxidants - pharmacokinetics
Antioxidants - pharmacology
Arteriosclerosis - prevention & control
Benzofurans - chemical synthesis
Benzofurans - pharmacokinetics
Benzofurans - pharmacology
Biological and medical sciences
Cardiovascular system
Free Radicals
General and cellular metabolism. Vitamins
Linoleic Acid - chemistry
Lipoproteins, LDL - blood
Lipoproteins, LDL - chemistry
Luminescent Measurements
Medical sciences
Miscellaneous
Oxidation-Reduction
Pharmacology. Drug treatments
Rabbits
Structure-Activity Relationship
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Summary:Antioxidants have been considered as potential antiatherogenic agents by inhibiting oxidation of low-density lipoprotein (LDL), albeit vitamin E, a natural antioxidant, has failed to show reduction on atherosclerosis in clinical trials. We have rationally designed and synthesized a novel series of antioxidants, 4,6-di-tert-butyl-2,3-dihydro-5-benzofuranols, to overcome the clinical limitation of vitamin E. In vitro, the compounds showed a potent inhibitory effect on lipid peroxidation detected as 2-methyl-6-(p-methoxyphenyl)-3,7-dihydroimidazo[1,2-a]pyrazin-3-one (MCLA)-dependent chemiluminescence in linoleic acid autoxidation. They also inhibited the LDL oxidation induced by Cu2+, and the inhibition is more potent than that of vitamin E and probucol. In vivo, 4,6-di-tert-butyl-2,3-dihydro-2,2-dipentyl-5-benzofuranol (BO-653, 1f), an optimal compound, showed the highest concentration in plasma and LDL fraction in Watanabe heritable hyperlipidemic rabbits, due to its high affinity to LDL. The isolated LDL samples from the 1f-treated rabbits showed potent resistibility to LDL oxidation. Compound 1f has been taken into clinical trials.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm030062a