title: NO-independent, haem-dependent soluble guanylate cyclase stimulators.
abstract: 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.
authors.affiliation: Bayer Schering Pharma AG, Cardiology Research, Pharma Research Center, Wuppertal, 42096, Germany. johannes-peter.stasch@bayerhealthcare.com
authors.forename: Johannes-Peter
authors.initials: JP
authors.lastname: Stasch
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Hobbs
mesh_terms: D000178:Acrylamides / Q000494:pharmacology; D000818:Animals; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000503:physiopathology; D002986:Clinical Trials as Topic; D020536:Enzyme Activators / Q000494:pharmacology*; D006162:Guanylate Cyclase / Q000187:drug effects* / Q000378:metabolism; D006418:Heme / Q000378:metabolism*; D006801:Humans; D007191:Indazoles / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction; D000071756:Soluble Guanylyl Cyclase
chemical_list: D000178:Acrylamides; D020536:Enzyme Activators; D007191:Indazoles; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; D009569:Nitric Oxide; D006418:Heme; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase