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 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.
Tamura
Kunio
K
Synthetic Technology Research Department, Chugai Pharmaceutical Co, Ltd, 5-5-1 Ukima, Kita-ku, Tokyo 115-8543, Japan.
Kato
Yoshiaki
Y
Ishikawa
Akira
A
Kato
Yasuharu
Y
Himori
Motomu
M
Yoshida
Mitsutaka
M
Takashima
Yoshiaki
Y
Suzuki
Tsukasa
T
Kawabe
Yoshiki
Y
Cynshi
Osamu
O
Kodama
Tatsuhiko
T
Niki
Etsuo
E
Shimizu
Makoto
M
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
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