Novel sGC Stimulators and sGC Activators for the Treatment of Heart Failure

Abstract

The burden of heart failure (HF) increases worldwide with an aging population, and there is a high unmet medical need in both, heart failure with reduced ejection fraction (HFrEF) and with preserved ejection fraction (HFpEF). The nitric oxide (NO) pathway is a key regulator in the cardiovascular system and modulates vascular tone and myocardial performance. Disruption of the NO-cyclic guanosine monophosphate (cGMP) signaling axis and impaired cGMP formation by endothelial dysfunction could lead to vasotone dysregulation, vascular and ventricular stiffening, fibrosis, and hypertrophy resulting in a decline of heart as well as kidney function. Therefore, the NO-cGMP pathway is a treatment target in heart failure. Exogenous NO donors such as nitrates have long been used for treatment of cardiovascular diseases but turned out to be limited by increased oxidative stress and tolerance. More recently, novel classes of drugs were discovered which enhance cGMP production by targeting the NO receptor soluble guanylate cyclase (sGC). These compounds, the so-called sGC stimulators and sGC activators, are able to increase the enzymatic activity of sGC to generate cGMP independently of NO and have been developed to target this important signaling cascade in the cardiovascular system.This review will focus on the role of sGC in cardiovascular (CV) physiology and disease and the pharmacological potential of sGC stimulators and sGC activators therein. Preclinical data will be reviewed and summarized, and available clinical data with riociguat and vericiguat, novel direct sGC stimulators, will be presented. Vericiguat is currently being studied in a Phase III clinical program for the treatment of heart failure with reduced ejection fraction (HFrEF).

Soluble Guanylate Cyclase Stimulators and Activators

“…In addition, the efficacy of PDE5i may be substantially limited under conditions of very low endogenous NO production, resulting in low intracellular cGMP production. Decoupling of the NOS/NO/cGMP signaling cascade and low NO/cGMP production has been shown in ED patients (Bivalacqua et al 2003) and also in patients with PAH and heart failure where endothelial dysfunction leads to impaired NO synthesis (Breitenstein et al 2017). The low endogenous NO production could be due to aging (Garbán et al 1995), but also metabolic syndrome, dyslipidemia (Mulhall et al 2006), and obesity with and without hypogonadism (Gurbuz et al 2008).…”

“…Nitrates have a long history of use in angina as well as acute and chronic heart failure, but their utility may be limited by development of tolerance and propensity to form highly damaging peroxynitrites. The rationale for treating both HFrEF and HFpEF with sGC agonists is strong and was recently reviewed (Breitenstein et al 2017). sGC is expressed in critical cardiovascular tissues including vascular smooth muscle, the heart, and the kidney, and sGC α1 À/À knockout mice have impaired ventricular relaxation and reduced cardiac output (Irvine et al 2012).…”

The Role of Nitroglycerin and Other Nitrogen Oxides in Cardiovascular Therapeutics

“…There are ongoing trials of riociguat’s potential role in the treatment of pulmonary hypertension and heart failure. Other NOsGC-stimulating ciguats that are being studied include vericiguat, which was shown to decreased circulating levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with worsening chronic systolic heart failure, as well as nelociguat, IW-1973, and IW-1701 (174,195,196). …”

Contemporary Approaches to Modulating the Nitric Oxide–cGMP Pathway in Cardiovascular Disease

“…As riociguate is eliminated within 7–12 hrs, the drug has to be taken 3 times daily which may impact patient compliance. Vericiguat, another NOsGC stimulator, shows an optimized pharmacokinetic profile and allows a once daily dosing regimen 95 . More recently, a dose-finding, phase 2 study (SOCRATES-REDUCED) demonstrated that vericiquat dose-dependently reduced circulating N-terminal pro-B-type natriuretic peptide (NT-proBNP), a biomarker for heart failure, in patients with chronic failure and reduced ejection fraction 96 .…”