title: Design and synthesis of 4,6-di-tert-butyl-2,3-dihydro-5-benzofuranols as a novel series of antiatherogenic antioxidants.
abstract: 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 Cu(2+), 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.
authors.affiliation: Synthetic Technology Research Department, Chugai Pharmaceutical Co, Ltd, 5-5-1 Ukima, Kita-ku, Tokyo 115-8543, Japan.
authors.forename: Kunio
authors.initials: K
authors.lastname: Tamura
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kato
authors.forename: Akira
authors.initials: A
authors.lastname: Ishikawa
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Kato
authors.forename: Motomu
authors.initials: M
authors.lastname: Himori
authors.forename: Mitsutaka
authors.initials: M
authors.lastname: Yoshida
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Takashima
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Suzuki
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Kawabe
authors.forename: Osamu
authors.initials: O
authors.lastname: Cynshi
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Kodama
authors.forename: Etsuo
authors.initials: E
authors.lastname: Niki
authors.forename: Makoto
authors.initials: M
authors.lastname: Shimizu
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001161:Arteriosclerosis / Q000517:prevention & control*; D001572:Benzofurans / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D005609:Free Radicals; D019787:Linoleic Acid / Q000737:chemistry; D008077:Lipoproteins, LDL / Q000097:blood / Q000737:chemistry; D008163:Luminescent Measurements; D010084:Oxidation-Reduction; D011817:Rabbits; D013329:Structure-Activity Relationship; D024502:alpha-Tocopherol / Q000494:pharmacology
chemical_list: C106512:2,3-dihydro-5-hydroxy-2,2-dipentyl-4,6-di-tert-butylbenzofuran; D000975:Antioxidants; D001572:Benzofurans; D005609:Free Radicals; D008077:Lipoproteins, LDL; D019787:Linoleic Acid; D024502:alpha-Tocopherol