Soluble Guanylate Cyclase Stimulators and Activators

Abstract

When Furchgott, Murad, and Ignarro were honored with the Nobel prize for the identification of nitric oxide (NO) in 1998, the therapeutic implications of this discovery could not be fully anticipated. This was due to the fact that available therapeutics like NO donors did not allow a constant and long-lasting cyclic guanylyl monophosphate (cGMP) stimulation and had a narrow therapeutic window. Now, 20 years later, the stimulator of soluble guanylate cyclase (sGC), riociguat, is on the market and is the only drug approved for the treatment of two forms of pulmonary hypertension (PAH/CTEPH), and a variety of other sGC stimulators and sGC activators are in preclinical and clinical development for additional indications. The discovery of sGC stimulators and sGC activators is a milestone in the field of NO/sGC/cGMP pharmacology. The sGC stimulators and sGC activators bind directly to reduced, heme-containing and oxidized, heme-free sGC, respectively, which results in an increase in cGMP production. The action of sGC stimulators at the heme-containing enzyme is independent of NO but is enhanced in the presence of NO whereas the sGC activators interact with the heme-free form of sGC. These highly innovative pharmacological principles of sGC stimulation and activation seem to have a very broad therapeutic potential. Therefore, in both academia and industry, intensive research and development efforts have been undertaken to fully exploit the therapeutic benefit of these new compound classes. Here we summarize the discovery of sGC stimulators and sGC activators and the current developments in both compound classes, including the mode of action, the chemical structures, and the genesis of the terminology and nomenclature. In addition, preclinical studies exploring multiple aspects of their in vitro, ex vivo, and in vivo pharmacology are reviewed, providing an overview of multiple potential applications. Finally, the clinical developments, investigating the treatment potential of these compounds in various diseases like heart failure, diabetic kidney disease, fibrotic diseases, and hypertension, are reported. In summary, sGC stimulators and sGC activators have a unique mode of action with a broad treatment potential in cardiovascular diseases and beyond.

Olinciguat, an Oral sGC Stimulator, Exhibits Diverse Pharmacology Across Preclinical Models of Cardiovascular, Metabolic, Renal, and Inflammatory Disease

“…sGC stimulators are a class of small molecule drugs that also target the NO-sGC-cGMP pathway (Sandner et al, 2018). The sGC stimulator riociguat is approved for the treatment of two rare and serious forms of pulmonary hypertension: pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (Ghofrani et al, 2013a;Ghofrani et al, 2013b).…”

“…The sGC stimulator riociguat is approved for the treatment of two rare and serious forms of pulmonary hypertension: pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (Ghofrani et al, 2013a;Ghofrani et al, 2013b). sGC stimulators have also shown benefit across a broad range of preclinical disease models including cardiac and kidney disease, pulmonary and skin fibrosis, metabolic disorders, and liver disease [reviewed in (Sandner et al, 2018)].…”

BAY 41-2272 Attenuates CTGF Expression via sGC/cGMP-Independent Pathway in TGFβ1-Activated Hepatic Stellate Cells

“…sGCs are expressed in HSCs and not in hepatocytes [50] and are divided into reduced and oxidized forms that possess heme-dependent and heme-independent properties, respectively [11,13]. Many sGC modulators have been developed: (1) sGC stimulators to sensitize the reduced and heme-containing sGC to NO, and (2) sGC activators to activate oxidized and heme-free sGC [51][52][53] to generate cGMP. Exposure of 8-Br-cGMP cGMP analog leads to an inhibition of TGFβ-induced fibrogenesis in renal, cardiac, and dermal fibroblasts [26,54,55], suggesting that the sGC/cGMP pathway may be preferential signaling for TGFβ-induced HSC activation.…”

Pharmacokinetics, mass balance, tissue distribution, metabolism, and excretion of praliciguat, a clinical‐stage soluble guanylate cyclase stimulator in rats

“…Praliciguat (IW‐1973) is a soluble guanylate cyclase (sGC) stimulator under development for the treatment of diabetic nephropathy (DN; ClinicalTrials.gov Identifier NCT03217591) and heart failure with preserved ejection fraction (HFpEF; ClinicalTrials.gov Identifier NCT03254485). sGC is a receptor for nitric oxide (NO) and plays a central physiological role in regulating blood flow, inflammation, and fibrosis 1,2 . Upon binding NO, sGC catalyzes the conversion of guanosine‐5′‐triphosphate (GTP) to the second messenger cyclic guanosine‐3′,5′‐monophosphate (cGMP) which in turn regulates multiple physiological processes 3 .…”