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

• 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
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm030062a

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.