Design, Synthesis, and Biological Evaluation of 1,4-Diaryl-1,4-dihydropyrazines as Novel 11β-HSD1 Inhibitors

Xiaowei Duan, Hongxing Xin, Hong Yan
2014 Biological and Pharmaceutical Bulletin  
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
more » ... ors 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.
doi:10.1248/bpb.b14-00070 pmid:24790006 fatcat:koych32eqvbrtk4rjm4lytqu3e