title: Benzofuran derivatives inhibit 11β-hydroxysteroid dehydrogenase type 1 activity in rat adipose tissue.
abstract: 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.
authors.affiliation: Department of Medical Biochemistry, Kobe Pharmaceutical University, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kiyonaga
authors.forename: Noriko
authors.initials: N
authors.lastname: Tagawa
authors.forename: Yuko
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Midori
authors.initials: M
authors.lastname: Wakabayashi
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Kogure
authors.forename: Masafumi
authors.initials: M
authors.lastname: Ueda
authors.forename: Okiko
authors.initials: O
authors.lastname: Miyata
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Kobayashi
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000378:metabolism*; D041721:3T3-L1 Cells; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology* / Q000627:therapeutic use; D003345:Corticosterone / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D050152:Intra-Abdominal Fat / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008643:Mesentery / Q000187:drug effects / Q000378:metabolism; D008659:Metabolic Diseases / Q000188:drug therapy; D051379:Mice; D008861:Microsomes / Q000187:drug effects; D009249:NADP / Q000378:metabolism; D009765:Obesity / Q000209:etiology / Q000517:prevention & control; D051381:Rats; D017208:Rats, Wistar
chemical_list: D001572:Benzofurans; D009249:NADP; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D003345:Corticosterone