Meeting report of the 8th International Conference on cGMP “cGMP: generators, effectors, and therapeutic implications” at Bamberg, Germany, from June 23 to 25, 2017

Friebe, Andreas; Sandner, Peter; Schmidtko, Achim

doi:10.1007/s00210-017-1429-5

Cited by 11 publications

(8 citation statements)

References 55 publications

(58 reference statements)

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“…Olinciguat and riociguat are also in Phase 2 trials in sickle cell disease patients (NCT03285178 and NCT02633397, respectively). In addition to these more advanced clinical programs, there are still other sGC stimulators in preclinical development that might increase the number of compounds available for the benefit of patients (Friebe et al 2017).…”

Section: Clinical Developments Of Sgc Stimulators and Sgc Activatorsmentioning

confidence: 99%

“…Bayer recently reported three sGC activators in Phase 1 with the intention of potentially treating chronic kidney disease pulmonary hypertension and acute respiratory distress syndrome (ARDS). In addition, Boehringer-Ingelheim (BI) recently reported the early development of an sGC activator for chronic kidney disease (Friebe et al 2017). It will become a very interesting topic in the future, how these compound class of sGC activatorsacting on the heme-free sGCcould be differentiated from sGC stimulators.…”

Section: Sgc Activatorsmentioning

confidence: 99%

“…However, sGC stimulators and sGC activators have shown beneficial effects in animal models of a variety of other disease conditions. At the cGMP conference held in Bamberg, Germany in June 2017, world experts discussed not only novel targets for cGMP, but also new therapeutic applications of sGC modulators (Friebe et al 2017). Although the details are beyond the scope of this chapter, some current and future lines of potential therapeutic applications are summarized below.…”

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confidence: 99%

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Soluble Guanylate Cyclase Stimulators and Activators

Sandner

Zimmer

Milne

et al. 2018

Handbook of Experimental Pharmacology

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131

149

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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.

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Section: Clinical Developments Of Sgc Stimulators and Sgc Activatorsmentioning

confidence: 99%

Section: Sgc Activatorsmentioning

confidence: 99%

mentioning

confidence: 99%

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Soluble Guanylate Cyclase Stimulators and Activators

Sandner

Zimmer

Milne

et al. 2018

Handbook of Experimental Pharmacology

Self Cite

131

149

View full text Add to dashboard Cite

show abstract

“…In recent years, the antifibrotic effects of cGMP have been intensively studied (Higuchi et al 2015;Matei et al 2018). At the 2017 cGMP conference, the preclinical effects of sGC stimulation and riociguat on skin fibrosis were presented Friebe et al 2017). At the present cGMP conference, the results of a phase 2 clinical program assessing the treatment effects of riociguat in SSc patients with diffuse systemic sclerosis were presented (Melanie Hemmrich, Wuppertal).…”

Section: Systemic Sclerosismentioning

confidence: 99%

cGMP: a unique 2nd messenger molecule – recent developments in cGMP research and development

Friebe

Sandner

Schmidtko

2019

Naunyn-Schmiedeberg's Arch Pharmacol

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101

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Cyclic guanosine monophosphate (cGMP) is a unique second messenger molecule formed in different cell types and tissues. cGMP targets a variety of downstream effector molecules and, thus, elicits a very broad variety of cellular effects. Its production is triggered by stimulation of either soluble guanylyl cyclase (sGC) or particulate guanylyl cyclase (pGC); both enzymes exist in different isoforms. cGMP-induced effects are regulated by endogenous receptor ligands such as nitric oxide (NO) and natriuretic peptides (NPs). Depending on the distribution of sGC and pGC and the formation of ligands, this pathway regulates not only the cardiovascular system but also the kidney, lung, liver, and brain function; in addition, the cGMP pathway is involved in the pathogenesis of fibrosis, inflammation, or neurodegeneration and may also play a role in infectious diseases such as malaria. Moreover, new pharmacological approaches are being developed which target sGC-and pGC-dependent pathways for the treatment of various diseases. Therefore, it is of key interest to understand this pathway from scratch, beginning with the molecular basis of cGMP generation, the structure and function of both guanylyl cyclases and cGMP downstream targets; research efforts also focus on the subsequent signaling cascades, their potential crosstalk, and also the translational and, ultimately, the clinical implications of cGMP modulation. This review tries to summarize the contributions to the "9th International cGMP Conference on cGMP Generators, Effectors and Therapeutic Implications" held in Mainz in 2019. Presented data will be discussed and extended also in light of recent landmark findings and ongoing activities in the field of preclinical and clinical cGMP research.

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“…NO-releasing organic nitrates have been used for the treatment of angina pectoris for more than a century. Novel functions of cGMP and clinical applications of cGMP-based drugs are continuously being discovered [ 75 , 76 ]. Indeed, drugs that increase cGMP concentration have emerged as one of the most successful areas in recent drug development and clinical pharmacology [ 77 , 78 ].…”

Section: Cgmp and Vascular Diseasesmentioning

confidence: 99%

cGMP Signaling and Vascular Smooth Muscle Cell Plasticity

Lehners

Dobrowinski

Feil

et al. 2018

JCDD

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Cyclic GMP regulates multiple cell types and functions of the cardiovascular system. This review summarizes the effects of cGMP on the growth and survival of vascular smooth muscle cells (VSMCs), which display remarkable phenotypic plasticity during the development of vascular diseases, such as atherosclerosis. Recent studies have shown that VSMCs contribute to the development of atherosclerotic plaques by clonal expansion and transdifferentiation to macrophage-like cells. VSMCs express a variety of cGMP generators and effectors, including NO-sensitive guanylyl cyclase (NO-GC) and cGMP-dependent protein kinase type I (cGKI), respectively. According to the traditional view, cGMP inhibits VSMC proliferation, but this concept has been challenged by recent findings supporting a stimulatory effect of the NO-cGMP-cGKI axis on VSMC growth. Here, we summarize the relevant studies with a focus on VSMC growth regulation by the NO-cGMP-cGKI pathway in cultured VSMCs and mouse models of atherosclerosis, restenosis, and angiogenesis. We discuss potential reasons for inconsistent results, such as the use of genetic versus pharmacological approaches and primary versus subcultured cells. We also explore how modern methods for cGMP imaging and cell tracking could help to improve our understanding of cGMP’s role in vascular plasticity. We present a revised model proposing that cGMP promotes phenotypic switching of contractile VSMCs to VSMC-derived plaque cells in atherosclerotic lesions. Regulation of vascular remodeling by cGMP is not only an interesting new therapeutic strategy, but could also result in side effects of clinically used cGMP-elevating drugs.

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Meeting report of the 8th International Conference on cGMP “cGMP: generators, effectors, and therapeutic implications” at Bamberg, Germany, from June 23 to 25, 2017

Cited by 11 publications

References 55 publications

Soluble Guanylate Cyclase Stimulators and Activators

Soluble Guanylate Cyclase Stimulators and Activators

cGMP: a unique 2nd messenger molecule – recent developments in cGMP research and development

cGMP Signaling and Vascular Smooth Muscle Cell Plasticity

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