Ongoing research on sGC stimulators led to the development of the more potent and more specific sGC stimulator, riociguat. 5 Recently, the US Food and Drug Administration Sunitinib has approved riociguat to treat PAH
in adults. Support for approval of riociguat comes from the recently published PATENT-1 (Pulmonary Arterial Hypertension Soluble Guanylate Cyclase–Stimulator Trial 1) study. 6 Soluble guanylate cyclase as a therapeutic target in PAH sGC is a dimeric, heme-containing, redox-sensitive enzyme that catalyzes the synthesis of the second messenger cGMP, which produces (through a number of downstream mechanisms) numerous biological effects, including vasorelaxation and inhibition of fibrosis, smooth muscle proliferation, apoptosis, leukocyte recruitment, and platelet aggregation. 5–8 NO binds to sGC only when the heme group on sGC is in the reduced ferrous state. Notably, binding of NO to the reduced heme group leads to an approximately 200-fold increase in the conversion of GTP to cGMP. 9 Alternatively, oxidation of this heme group results in its dissociation from the enzyme and the generation of NO-insensitive sGC. 10 In the presence of an intact heme-moiety, the sGC is a constitutively active enzyme that basally releases cGMP. 11
However in PAH, although the total sGC expression is increased, alteration of the redox state of sGC through oxidative stress may lead to reduced levels of the NO-sensitive form of sGC. 12 sGC agonists are divided in two different categories according to their mechanism of action 5–13 : (1) sGC stimulators sensitize sGC to NO by stabilizing the binding site on sGC. Accordingly, action of sGC stimulators is dependent on the presence of a reduced heme (heme-dependent compounds such as riociguat) (2)
sGC activators preferentially and effectively activate sGC when it is in an oxidized (heme-independent compounds such as cinaciguat) Riociguat is the first drug approved in the new class of sGC stimulators. Riociguat acts through a dual mechanism: (1) direct stimulation of sGC in a NO independent fashion, and (2) by sensitization of sGC to low endogenous NO levels. 14 In experimental studies, riociguat stimulated recombinant sGC up to Brefeldin_A 73-fold, and in the presence of a NO-releasing agent, increased the activity of sGC 112-fold above baseline. 15 Pre-clinical studies with sGC stimulators have shown vasodilatory, antiproliferative, antifibrotic, and antiinflammatory effects. 5–16 Patent-1 PATENT-1 6 is a double-blind, randomized, placebo-controlled trial of 443 patients with PAH at 124 centers in 30 countries. Patients were randomly assigned in 2:4:1 ratio to; placebo, riociguat in individually adjusted doses up to 2.5 mg three times daily (2.5 mg maximum group), or riociguat in individually adjusted doses that were capped at 1.5 mg three times daily (1.5 mg maximum group). The 1.