Clinical relevance of cyclic GMP modulators: A translational success story of network pharmacology

  title={Clinical relevance of cyclic GMP modulators: A translational success story of network pharmacology},
  author={Jeannette Oettrich and Vu Thao-Vi Dao and Jeroen Frijhoff and Pwm Kleikers and Ana I. Casas and Adrian J. Hobbs and Harald H.H.W. Schmidt},
  journal={Clinical Pharmacology \& Therapeutics},
Therapies that modulate cyclic guanosine‐3′‐5′‐monophosphate (cGMP) have emerged as one of the most successful areas in recent drug discovery and clinical pharmacology. Historically, their focus has been on cardiovascular disease phenotypes; however, cGMP's relevance is likely to go beyond this rather limited organ‐based set of indications. Moreover, the multitude of targets and their apparent interchangeability is a proof‐of‐concept of network pharmacology. 
Cyclic GMP modulating drugs in cardiovascular diseases: Mechanism-based network pharmacology.
A glimpse into the future is provided on how drugs interfering with this pathway may change how the authors treat and diagnose cardiovascular diseases altogether and the detection of cGMPopathy endotypes amongst cardiovascular disease phenotypes.
A diseasome cluster-based drug repurposing of soluble guanylate cyclase activators from smooth muscle relaxation to direct neuroprotection
Here, Schmidt and co-workers show that, based on this principle, a cardio-pulmonary drug can be surprisingly repurposed for a previously not recognised application as a direct neuroprotectant and find that the cyclic GMP forming soluble guanylate cyclase becomes dysfunctional upon stroke but regains catalytic activity in the presence of specific activator compounds.
Meeting report of the 8th International Conference on cGMP “cGMP: generators, effectors, and therapeutic implications” at Bamberg, Germany, from June 23 to 25, 2017
At the 8th International Conference on cGMP, held in Bamberg, Germany, world leading experts came together to discuss these topics and all aspects ofcGMP research from the basic understanding of cG MP signaling to clinical applicability were discussed in depth.
Design and optimization of purine derivatives as in vivo active PDE10A inhibitors.
Two inhibitors are identified as interesting lead compounds with the potential for further PDE10A lead optimizatioin after several rounds of optimization and in vivo pharmacological tests.
cGMP Signaling and Vascular Smooth Muscle Cell Plasticity
A revised model proposing that cGMP promotes phenotypic switching of contractile VSMCs to VSMC-derived plaque cells in atherosclerotic lesions is presented, which could result in side effects of clinically used cG MP-elevating drugs.
GPCRs Are Optimal Regulators of Complex Biological Systems and Orchestrate the Interface between Health and Disease
The molecular diversity of GPCR signaling systems is likely to be closely associated with disease-associated changes in organismal tissue complexity and compartmentalization, thus enabling a nuanced G PCR-based capacity to interdict multiple disease pathomechanisms at a systemic level.
Visualising and understanding cGMP signals in the cardiovascular system.
CGMP's multifaceted role in (patho-)physiology and pharmacotherapy is outlined, and what new insights cG MP imaging has provided into endogenous cGMP signalling and drug action are summarized, with a focus on the cardiovascular system.
Systems Biology: Methods and Applications
A detailed overview of recent high-throughput profiling technologies and computational modeling approaches is provided to provide the foundations to further integrate systems biology approaches into biomedical research.
Endothelial SIRT1 prevents age-induced impairment of vasodilator responses by enhancing the expression and activity of soluble guanylyl cyclase in smooth muscle cells
Enhancing the endothelial expression and function of SIRT1 prevents early vascular ageing and maintains vasodilator responses, thus representing promising drug targets for cardiovascular diseases.
Correction to: Meeting report of the 8th International Conference on "cGMP BcGMP: generators, effectors, and therapeutic implications" at Bamberg, Germany, from June 23 to 25, 2017
The article “Meeting report of the 8thInternational Conference on "cGMP BcGMP: generators, effectors, and therapeutic implications" at Bamberg, Germany, from June 23 to 25, 2017” was originally


Sildenafil in hypoxic pulmonary hypertension potentiates a compensatory up‐regulation of NO‐cGMP signaling
NO‐cGMP signaling is compensatorily up‐regulated in the hypoxic mouse model of PH, and sildenafil further augments this pathway to functionally alleviate pulmonary vasocon‐striction.
Targeting the heme-oxidized nitric oxide receptor for selective vasodilatation of diseased blood vessels.
It is shown in vivo that oxidative stress and related vascular disease states, including human diabetes mellitus, led to an sGC that was indistinguishable from the in vitro oxidized/heme-free enzyme, and BAY 58-2667 was more effective and potentiated under pathophysiological and oxidative stress conditions.
Measuring oxidative burden and predicting pharmacological response in coronary artery disease patients with a novel direct activator of haem-free/oxidised sGC.
Two platelet-based assays are described that allow the determination of patients' oxidative status and thus allow the prediction of pharmacological response to direct sGC activators.
Dysfunctional nitric oxide signalling increases risk of myocardial infarction
Starting with a severely affected family, this work has identified a link between impaired soluble-guanylyl-cyclase-dependent nitric oxide signalling and myocardial infarction risk, possibly through accelerated thrombus formation, and demonstrated in vitro that mutations in both GUCY1A3 and CCT7 severely reduce α1-sGC as well as β1- sGC protein content, and impair soluble guanyly l cyclase activity.
A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation.
The new HFPEF paradigm proposes comorbidities, plasma markers of inflammation, or vascular hyperemic responses to be included in diagnostic algorithms and aims at restoring myocardial PKG activity.