NO-independent stimulators and activators of soluble guanylate cyclase: discovery and therapeutic potential

Key Points

  • Soluble guanylate cyclase (sGC) is a key signal-transduction enzyme, which converts GTP to the second messenger cGMP in response to signalling from gaseous ligands, particularly nitric oxide (NO).

  • Alterations of the NO–sGC–cGMP pathway are implicated in a number of cardiovascular and other diseases; however, current therapies for these conditions involving NO-releasing drugs have a number of significant limitations.

  • Two NO-independent pharmacological modalities (sGC stimulators and sGC activators) have been recently developed.

  • Haem-dependent, direct sGC stimulators sensitize the reduced form of sGC to endogenous and exogenous NO.

  • Haem-independent, direct sGC activators re-activate oxidized or haem-free states of sGC that have become unresponsive to NO as a result of disease processes (such as oxidative stress).

  • These compounds have greatly enhanced our understanding of the NO–sGC–cGMP signalling pathway and, for the first time, mechanism-based vasodilators specific for diseased blood vessels have become available.

  • Pharmacological stimulation/activation of sGC could be useful for chronic therapy of cardiovascular diseases that was previously limited by the development of tolerance following prolonged administration of conventional NO-based vasodilators.

  • Pulmonary hypertension and essential hypertension could be the first clinical applications for sGC stimulators, whereas heart failure might be the first clinical application for sGC activators.

  • Non-vascular applications could further extend the spectrum of clinical indications and direct sGC activators might also be useful in vascular response diagnostics.

Abstract

Soluble guanylate cyclase (sGC) is a key signal-transduction enzyme activated by nitric oxide (NO). Impaired bioavailability and/or responsiveness to endogenous NO has been implicated in the pathogenesis of cardiovascular and other diseases. Current therapies that involve the use of organic nitrates and other NO donors have limitations, including non-specific interactions of NO with various biomolecules, lack of response and the development of tolerance following prolonged administration. Compounds that activate sGC in an NO-independent manner might therefore provide considerable therapeutic advantages. Here we review the discovery, biochemistry, pharmacology and clinical potential of haem-dependent sGC stimulators (including YC-1, BAY 41-2272, BAY 41-8543, CFM-1571 and A-350619) and haem-independent sGC activators (including BAY 58-2667 and HMR-1766).

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Figure 1: The NO–sGC–cGMP signal transduction pathway and potential drug targets.
Figure 2: Homology model of the haem-binding domain of the human soluble guanylate cyclase (sGC) β-subunit.
Figure 3: Soluble guanylate cyclase (sGC) redox equilibrium.
Figure 4: NO–sGC–cGMP signalling in a blood vessel.

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Acknowledgements

The authors thank P. Sexton for generating the sGC homology model. This publication was supported in part by the National Heart, Lung, and Blood Institute and the Intramural Research Program of National Institutes of Health (USA) and the Alexander von Humboldt Foundation (Germany).

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Correspondence to Oleg V. Evgenov.

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Competing interests

O.V.E. is a co-inventor of a pending patent application on enhancing the effectiveness of an inhaled therapeutic gas by using sGC stimulators. P.M.S. was employed by Bayer HealthCare from 2000 to 2003. H.H.H.W.S. is a co-inventor of a patent on the use of human sGC, owned by Vasopharm GmbH, and he holds shares in that company. J.-P.S. is a full time employee of Bayer HealthCare. He has filed several patent applications on sGC stimulators (for example, BAY 41-2272 and BAY 41-8543) and sGC activators (for example, BAY 58-2667). P.P. and G. H. have no competing interests that might be perceived to influence the results and discussion reported in this paper.

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Glossary

Haem-binding domain

A conserved domain, present in various proteins that are involved in gas and/or redox sensing, that can bind a prosthetic haem moiety, which is, in turn, responsible for binding gaseous ligands such as NO, O2 or CO.

Prosthetic haem moiety

Haem is the prosthetic group of various gas and/or redox-sensing proteins and consists of a large heterocyclic organic ring called porphyrin and a central metal atom (for example, iron, copper or zinc).

Redox state

A term used to reflect the oxidation state of the prosthetic haem moiety of sGC, which can exist in a reduced (ferrous; Fe2+) or an oxidized (ferric; Fe3+) state. The oxidized form of sGC is insensitive to NO.

Reactive oxygen species

Collective term for highly reactive molecules formed by the incomplete one-electron reduction of oxygen, and the products of further potential reactions (for example with NO). They include singlet oxygen, superoxide, peroxides, hydroxyl radical, peroxynitrite and hypochlorous acid.

EC50

The molecular concentration of an agonist that is required to produce 50% of the maximum response to that agonist.

K d

The equilibrium dissociation constant of a compound that reflects the concentration needed to reach half-maximal saturation of binding sites. Kd reflects the strength of binding of a compound to its specific binding site.

Spatial structure

The occupation of three-dimensional space by a given chemical compound or protein.

Porphyrin

A heterocyclic macrocycle made from four pyrrole rings joined by methine bridges (=CH-).

Methaemoglobinaemia

The presence of increased concentrations of methaemoglobin (resulting from the oxidation of haemoglobin) in blood. Methaemoglobin lacks the electron that is needed to form a bond with oxygen and is therefore incapable of oxygen transport to tissues.

Cardiac index

The volume of blood pumped by the heart every minute normalized to body surface area.

Restenosis

A re-narrowing of an artery at the site of angioplasty or stent placement.

Autocoid

A substance, such as a hormone, produced in one part of an organism and transported by blood or lymph to another part of the organism where it exerts a physiological effect.

Neointima

A new layer of endothelial cells on the inner surface of a blood vessel graft or a vascular prosthesis.

Mesangial cells

Phagocytic cells found in the mesangium of the glomerular capsule of the kidney that are thought to aid in cleaning the filtration apparatus.

Hepatic stellate cells

Cells that reside between the parenchymal cells and sinusoidal endothelial cells of the hepatic lobule and are the major storage site of vitamin A. In chronic liver injury (for example, chronic hepatitis), these hepatic cells produce collagen and other extracellular matrix proteins that lead to liver fibrosis and cirrhosis.

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Evgenov, O., Pacher, P., Schmidt, P. et al. NO-independent stimulators and activators of soluble guanylate cyclase: discovery and therapeutic potential. Nat Rev Drug Discov 5, 755–768 (2006). https://doi.org/10.1038/nrd2038

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