Benzofuran Derivatives Inhibit 11β-Hydroxysteroid Dehydrogenase Type 1 Activity in Rat Adipose Tissue
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概要
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Excess glucocorticoids promote visceral obesity and insulin resistance. The main regulator of intracellular glucocorticoid levels are 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which converts inactive glucocorticoid into bioactive glucocorticoid such as cortisol in humans and corticosterone in rodents; therefore, the inhibition of 11β-HSD1 has considerable therapeutic potential for metabolic diseases including obesity and diabetes. Benzofuran is a key structure in many biologically active compounds such as benzbromarone, malibatol A and (+)-liphagal. The aim of this study was to investigate the inhibitory effect of benzofuran derivatives on 11β-HSD1 in mesenteric adipose tissue from rodents. 11β-HSD1 activity was determined by incubation of rat mesenteric adipose tissue microsomes in the presence of reduced nicotinamide adenine dinucleotide phosphate (NADPH) with and without benzofuran derivatives (Compounds 1–14). The corticosterone produced was measured by HPLC. More than 40% of 11β-HSD1 inhibition was observed in Compounds 1, 5, 7 and 8. Moreover, Compounds 7 and 8 inhibited the 11β-HSD1 activity in adipose microsomes dose- and time-dependently, as well as in 3T3-L1 adipocytes. Compounds 7 and 8 did not inhibit 11β-HSD type 2 (11β-HSD2), whereas Compounds 1 and 5 inhibited 11β-HSD2 by 18.7% and 56.3%, respectively. Further, a kinetic study revealed that Compounds 7 and 8 acted as non-competitive inhibitors of 11β-HSD1. Ki (nmol/h/mg protein) values of Compounds 7 and 8 were 17.5 and 24.0, respectively, with IC50 (µM) of 10.2 and 25.6, respectively. These data indicate that Compounds 7 and 8 are convincing candidates for seed compounds as specific inhibitors of 11β-HSD1 and have the potential to be developed as anti-obesity drugs.
- 公益社団法人 日本薬学会の論文
著者
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Kogure Toshiaki
Department Of Integrated Japanese Oriental Medicine Faculty Of Medicine Gunma University School Of M
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Kobayashi Yoshiharu
Department Of Medical Biochemistry Kobe Pharmaceutical University
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TAGAWA Noriko
Department of Medical Biochemistry Kobe Pharmaceutical University
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Kiyonaga Daisuke
Department of Medical Biochemistry, Kobe Pharmaceutical University
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Yamaguchi Yuko
Department of Medical Biochemistry, Kobe Pharmaceutical University
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Wakabayashi Midori
Department of Medical Biochemistry, Kobe Pharmaceutical University
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Ueda Masafumi
Department of Medicinal Chemistry, Kobe Pharmaceutical University
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Miyata Okiko
Department of Medicinal Chemistry, Kobe Pharmaceutical University
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Kogure Toshiaki
Department of Medical Biochemistry, Kobe Pharmaceutical University
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