NO- and haem-independent soluble guanylate cyclase activators

Abstract

Oxidative stress, a risk factor for several cardiovascular disorders, interferes with the NO/sGC/cGMP signalling pathway through scavenging of NO and formation of the strong intermediate oxidant, peroxynitrite. Under these conditions, endothelial and vascular dysfunction develops, culminating in different cardio-renal and pulmonary-vascular diseases. Substituting NO with organic nitrates that release NO (NO donors) has been an important principle in cardiovascular therapy for more than a century. However, the development of nitrate tolerance limits their continuous clinical application and, under oxidative stress and increased formation of peroxynitrite foils the desired therapeutic effect. To overcome these obstacles of nitrate therapy, direct NO- and haem-independent sGC activators have been developed, such as BAY 58-2667 (cinaciguat) and HMR1766 (ataciguat), showing unique biochemical and pharmacological properties. Both compounds are capable of selectively activating the oxidized/haem-free enzyme via binding to the enzyme's haem pocket, causing pronounced vasodilatation. The potential importance of these new drugs resides in the fact that they selectively target a modified state of sGC that is prevalent under disease conditions as shown in several animal models and human disease. Activators of sGC may be beneficial in the treatment of a range of diseases including systemic and pulmonary hypertension (PH), heart failure, atherosclerosis, peripheral arterial occlusive disease (PAOD), thrombosis and renal fibrosis. The sGC activator HMR1766 is currently in clinical development as an oral therapy for patients with PAOD. The sGC activator BAY 58-2667 has demonstrated efficacy in a proof-of-concept study in patients with acute decompensated heart failure (ADHF), reducing pre- and afterload and increasing cardiac output from baseline. A phase IIb clinical study for the indication of ADHF is currently underway.