New Pharmacological Strategies to Increase cGMP

Abstract

The intracellular nucleotide cyclic guanosine monophosphate (cGMP) is found in many human organ tissues. Its concentration increases in response to the activation of receptor enzymes called guanylyl cyclases (GCs). Different ligands bind GCs, generating the second messenger cGMP, which in turn leads to a variety of biological actions. A deficit or dysfunction of this pathway at the cardiac, vascular, and renal levels manifests in cardiovascular diseases such as heart failure, arterial hypertension, and pulmonary arterial hypertension. An impairment of the cGMP pathway also may be involved in the pathogenesis of obesity as well as dementia. Therefore, agents enhancing the generation of cGMP for the treatment of these conditions have been intensively studied. Some have already been approved, and others are currently under investigation. This review discusses the potential of novel drugs directly or indirectly targeting cGMP as well as the progress of research to date.

The FOXO3/PGC-1β signaling axis is essential for cancer stem cell properties of pancreatic ductal adenocarcinoma

“…Several approaches have been established to indirectly or directly up-regulate intracellular cGMP for the treatment of other diseases, including erectile dysfunction, pulmonary hypertension, and cardiovascular disease (30). In addition, nitrites up-regulate cGMP levels through the release of nitric oxide and result in the activation of soluble guanylyl cyclase (31).…”

Drug‐Loaded Multifunctional Nanoparticles Targeted to the Endocardial Layer of the Injured Heart Modulate Hypertrophic Signaling

“…Here, PEGylated and indium ( 111 In)-labeled PSi nanoparticles functionalized with ANP are fabricated to specifically target the myocardial NPRs. [25] To achieve a sufficient colloidal stability and prolonged blood circulation time, functionalized undecylenic acid thermally hydrocarbonized PSi (UnTHCPSi) nanoparticles are used, [26] followed by surface modification with NH 2 PEGCO 2 H using crosslinking chemistry, to obtain PEGylated PSi (Un-P) nanoparticles. The Un-P nanoparticles were further modified with the trivalent metal chelator p-NH 2 B n DOTAtetra(t-Bu-ester) (Un-P-D) for radiolabeling and in vivo imaging purposes.…”

The soluble guanylate cyclase stimulator IW‐1973 prevents inflammation and fibrosis in experimental non‐alcoholic steatohepatitis

“…Cyclic nucleotides, such as cGMP, play a major role in cell signalling and tissue homeostasis. Pharmacological modulation of the cGMP pathway is a potential target for therapy in complex diseases Buglioni and Burnet, 2016). Indeed, small molecules with the ability to activate/stimulate soluble guanylate cyclase (sGC), which produces the second messenger cGMP in response to NO binding, have been reported to be therapeutically efficacious in several conditions, including pulmonary hypertension and chronic thromboembolic pulmonary hypertension (Ghofrani et al, 2013a,b).…”

“…Alterations in the NO-sGC-cGMP pathway resulting in increased tissue cGMP concentrations can be induced by four different interventions, namely, through the use of (i) specific PDE5 and PDE9 inhibitors, (ii) NO donors, (iii) sGC activators and (iv) sGC stimulators Buglioni and Burnet, 2016). PDE5 inhibitors, which prevent cGMP hydrolysis, were unable to enhance the exercise capacity of patients with heart failure (Redfield et al, 2013), and NO donors depend on a patient's biometabolism to be activated (Buglioni and Burnet, 2016). In contrast, direct sGC stimulators and activators provide a feasible alternative for the pharmacological manipulation of the NO-sGC-cGMP pathway.…”