Design, synthesis, and biological evaluation of 1,4-diaryl-1,4-dihydropyrazines as novel 11β-HSD1 inhibitors.
The inhibition of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) has demonstrated potential for the treatment of various components of metabolic syndrome. In this study, a series of 1,4-diaryl-1,4-dihydropyrazines were designed as inhibitors of 11β-HSD1 based on the structure-activity relationship of known 11β-HSD1 inhibitors through docking simulations. The docking simulation results supported the initial pharmacophore hypothesis: the docking results of the known inhibitors with 11β-HSD1 suggested a similar interaction of 1,4-diaryl-1,4-dihydropyrazines with the catalytic site of 11β-HSD1. Twelve of these compounds were synthesized through the cyclization of N,N-dialkylanilines with anilines, and their structures were determined by (1)H-NMR, (13)C-NMR, high resolution (HR)-MS, and single-crystal X-ray diffraction. The inhibitory activities of these compounds against human 11β-HSD1 were investigated in vitro through a scintillation proximity assay using microsomes containing 11β-HSD1.
College of Life Science and Bio-engineering, Beijing University of Technology.
Xiaowei
X
Duan
Hongxing
H
Xin
Hong
H
Yan
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D008958:Models, Molecular; D011719:Pyrazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D011719:Pyrazines; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1