Design, synthesis, and biological evaluation of 1,4-diaryl-1,4- dihydropyrazines as novel 11-βHSD1 inhibitors

Abstract

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 1H-NMR, 13C- 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. © 2014 The Pharmaceutical Society of Japan.