ArticleFrontiers in pharmacology2021
The CNS-Penetrant Soluble Guanylate Cyclase Stimulator CY6463 Reveals its Therapeutic Potential in Neurodegenerative Diseases.
Article in Frontiers in pharmacology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 33 citations in OpenAlex.
- First-in-human trial to assess safety, tolerability, pharmacokinetics, and pharmacodynamics of zagociguat (CY6463), a CNS-penetrant soluble guanylyl cyclase stimulator.Clinical and translational science · 2023Trial
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- A Framework for Selecting Zebrafish Models of Metabolic Diseases: Modeling Strategies, Phenotypic Validation, Mechanistic Investigation, and Efficacy Evaluation.Biomedicines · 2026Review
- Novel effects of vericiguat, alone and combined with high-intensity interval training, on brain function in mice with breast cancer: a histopathological and behavioral study.Naunyn-Schmiedeberg's archives of pharmacology · 2026Article
- Therapies for Mitochondrial Disease: Past, Present, and Future.Journal of inherited metabolic disease · 2025Review
- Zagociguat prevented stressor-induced neuromuscular dysfunction, improved mitochondrial physiology, and increased exercise capacity in diverse mitochondrial respiratory chain disease zebrafish models.Frontiers in pharmacology · 2025Article
- Discovery of a small molecule secreted clusterin enhancer that improves memory in Alzheimer's disease mice.npj drug discovery · 2025Article
- The evolution of small molecule enzyme activators.RSC medicinal chemistry · 2023Review
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- The 10th International Conference on cGMP 2022: recent trends in cGMP research and development-meeting report.Naunyn-Schmiedeberg's archives of pharmacology · 2023Review
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- Obesogenic Diet-Induced Neuroinflammation: A Pathological Link between Hedonic and Homeostatic Control of Food Intake.International journal of molecular sciences · 2023Review
- Mitochondrion-targeted RNA therapies as a potential treatment strategy for mitochondrial diseases.Molecular therapy. Nucleic acids · 2022Review
- Clinical Trials of New Drugs for Vascular Cognitive Impairment and Vascular Dementia.International journal of molecular sciences · 2022Review
- The Interplay between cGMP and Calcium Signaling in Alzheimer's Disease.International journal of molecular sciences · 2022Review
- The sGC stimulator BAY-747 and activator runcaciguat can enhance memory in vivo via differential hippocampal plasticity mechanisms.Scientific reports · 2022Article
- Neurovascular Dysfunction in Diverse Communities With Health Disparities-Contributions to Dementia and Alzheimer's Disease.Frontiers in neuroscience · 2022Review
- The CNS-penetrant soluble guanylate cyclase stimulator CYR119 attenuates markers of inflammation in the central nervous system.Journal of neuroinflammation · 2021Article
- Soluble Guanylate Cyclase Stimulator Vericiguat Enhances Long-Term Memory in Rats without Altering Cerebral Blood Volume.Biomedicines · 2021Article
Corrections and comments
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Authors and funding
19 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Effective treatments for neurodegenerative diseases remain elusive and are critically needed since the burden of these diseases increases across an aging global population. Nitric oxide (NO) is a gasotransmitter that binds to soluble guanylate cyclase (sGC) to produce cyclic guanosine monophosphate (cGMP). Impairment of this pathway has been demonstrated in neurodegenerative diseases. Normalizing deficient NO-cGMP signaling could address multiple pathophysiological features of neurodegenerative diseases. sGC stimulators are small molecules that synergize with NO, activate sGC, and increase cGMP production. Many systemic sGC stimulators have been characterized and advanced into clinical development for a variety of non-central nervous system (CNS) pathologies. Here, we disclose the discovery of CY6463, the first brain-penetrant sGC stimulator in clinical development for the treatment of neurodegenerative diseases, and demonstrate its ability to improve neuronal activity, mediate neuroprotection, and increase cognitive performance in preclinical models. In several cellular assays, CY6463 was demonstrated to be a potent stimulator of sGC. In agreement with the known effects of sGC stimulation in the vasculature, CY6463 elicits decreases in blood pressure in both rats and mice. Relative to a non-CNS penetrant sGC stimulator, rodents treated with CY6463 had higher cGMP levels in cerebrospinal fluid (CSF), functional-magnetic-resonance-imaging-blood-oxygen-level-dependent (fMRI-BOLD) signals, and cortical electroencephalographic (EEG) gamma-band oscillatory power. Additionally, CY6463 improved cognitive performance in a model of cognitive disruption induced by the administration of a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. In models of neurodegeneration, CY6463 treatment increased long-term potentiation (LTP) in hippocampal slices from a Huntington's disease mouse model and decreased the loss of dendritic spines in aged and Alzheimer's disease mouse models. In a model of diet-induced obesity, CY6463 reduced markers of inflammation in the plasma. Furthermore, CY6463 elicited an additive increase in cortical gamma-band oscillatory power when co-administered with donepezil: the standard of care in Alzheimer's disease. Together, these data support the clinical development of CY6463 as a novel treatment for neurodegenerative disorders.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.