Synthesis and characterization of NS-2028 analogues

Background Soluble guanylyl cyclase (sGC) is a ubiquitously expressed enzyme that synthesizes the second messenger cGMP. sGC has low basal activity which can be stimulated several hundred-fold by nitric oxide. Although, many NO activators and stimulators have been described only two chemically related sGC inhibitors exist: ODQ and NS-2028. The use of the above mentioned sGC inhibitors has helped researchers unravel many of the actions of the NO/ sGC/cGMP pathway. The mechanism of action of NS2028 and ODQ is believed to involve oxidation of the heme iron, making sGC unresponsive to NO. The aim of the present work was to sythesize and characterize a number of NS-2028 analogues for their ability to inhibit sGC. To this end 5 such analogues were generated and are shown below in Figure 1.