cGMP: Generators, Effectors and Therapeutic Implications

Stasch JP, Hobbs AJ, Johannes-Peter Stasch, Adrian J. Hobbs, Stasch, Johannes-Peter, Hobbs, Adrian J.

The nitric oxide (NO) signalling pathway is altered in cardiovascular diseases, including systemic and pulmonary hypertension, stroke, and atherosclerosis. The vasodilatory properties of NO have been exploited for over a century in cardiovascular disease, but NO donor drugs and inhaled NO are associated with significant shortcomings, including resistance to NO in some disease states, the development of tolerance during long-term treatment, and non-specific effects such as post-translational modification of proteins. The development of pharmacological agents capable of directly stimulating the NO receptor, soluble guanylate cyclase (sGC), is therefore highly desirable. The benzylindazole compound YC-1 was the first sGC stimulator to be identified; this compound formed a lead structure for the development of optimized sGC stimulators with improved potency and specificity for sGC, including CFM-1571, BAY 41-2272, BAY 41-8543, and BAY 63-2521. In contrast to the NO- and haem-independent sGC activators such as BAY 58-2667, these compounds stimulate sGC activity independent of NO and also act in synergy with NO to produce anti-aggregatory, anti-proliferative, and vasodilatory effects. Recently, aryl-acrylamide compounds were identified independent of YC-1 as sGC stimulators; although structurally dissimilar to YC-1, they have a similar mode of action and promote smooth muscle relaxation. Pharmacological stimulators of sGC may be beneficial in the treatment of a range of diseases, including systemic and pulmonary hypertension, heart failure, atherosclerosis, erectile dysfunction, and renal fibrosis. An sGC stimulator, BAY 63-2521, is currently in clinical development as an oral therapy for patients with pulmonary hypertension. It has demonstrated efficacy in a proof-of-concept study, reducing pulmonary vascular resistance and increasing cardiac output from baseline. A full, phase 2 trial of BAY 63-2521 in pulmonary hypertension is underway.