Synthesis and biological activity of two oxireno-azecin-imidazole derivatives on perfusion pressure via guanylate cyclase inhibition

Some drugs have used in the treatment of heart failure; however, several of these drugs can produce secondary effects such as arrhythmia, hypotension and others. Therefore, the objective of this study was to synthesize two oxireno-azecin-imidazole derivatives (compounds 13 and 14) from two estradiol and estrone analogs through a series of reactions which involving; a) addition; b) acetylation; c) epoxidation; d) formation of two azecine derivatives; e) removal of silyl fragment of the azecines with hydrofluoric acid. Additionally, these compounds were confirmed by NMR spectroscopic data. Then, biological activity of the oxireno-diazepam-imidazole derivatives against perfusion pressure was evaluate in an isolated rat heart model, using the BAY-41-2272 (guanylate cyclase agonist), NS-2028 (guanylate cyclase inhibitor) and nifedipine (calcium channel antagonist) as controls. The results indicate that compounds 13 and 14 increased the perfusion pressure in the absence or presence of BAY-41-2272 and NS-2028; however, this effect was inhibited by nifedipine. These data indicate that compounds 13 and 14 could have a dual effect on perfusion pressure through guanylate cyclase inhibition and calcium channel type-L activation.