The CNS-Penetrant Soluble Guanylate Cyclase Stimulator CY6463 Reveals its Therapeutic Potential in Neurodegenerative Diseases

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.

Soluble Guanylate Cyclase Stimulator Vericiguat Enhances Long-Term Memory in Rats without Altering Cerebral Blood Volume

“…Similar to our study, vericiguat reduced MAP, albeit in a 10x higher dose-range. The effective vericiguat doses in the study by Correia et al [69] are significantly higher than our memory-enhancing effective dose of 0.3 mg/kg. However, the differences between the brain-penetrant sGC stimulator CY6463 and the non-penetrant sGC stimulator vericiguat suggest mechanistically different pathways in memory enhancement.…”

“…However, it is likely that its very narrow therapeutic window on cognition could also play a role, i.e., the optimum dose for a (likely peripheral) effect was missed. Interestingly, in a recent study Correia et al [69] compared the novel brain penetrant sGC stimulator CY6463 to vericiguat and discovered that vericiguat did not increase cGMP levels in the CSF of rats after oral dosing with 30 mg/kg. In addition, altered fMRI-BOLD signals were found in only peripheral cortical regions after intravenous infusion of 3 mg/kg.…”

The CNS-penetrant soluble guanylate cyclase stimulator CYR119 attenuates markers of inflammation in the central nervous system

“…In rats, CYR119 increased cGMP levels in CSF after oral dosing, consistent with results from preclinical studies of the clinical-stage CNS-penetrant sGC stimulator CY6463, which also demonstrated an increased in CSF cGMP. The ability of CNS-penetrant sGC stimulators to increase cGMP levels in the CSF is in contrast to that of CNS-restricted sGC stimulators that do not alter CSF cGMP levels [ 9 ]. Consistent with previous work showing that increased NO–sGC signaling can modulate inflammation [ 18 , 23 ], we found that CYR119 reduced the LPS-induced inflammatory response in cultured microglial cells, reduced QA-induced neuroinflammation in rats [ 15 ], and reduced inflammatory gene expression in a DIO mouse model that is an established model of neuroinflammation [ 24 ].…”

“…These results are consistent with previous work showing that in a mouse model of cerebral malaria, treatment with an NO-donor decreased expression of ICAM-1 and P-selectin in the brain [ 31 ]. Future work with CYR119 or another CNS-penetrant sGC stimulator such as CY6463 [ 9 ] in additional models with more pronounced cytokine expression will increase the understanding of the role of the NO–sGC–cGMP pathway in neuroinflammation.…”

“…However, the effects of sGC stimulation on inflammation in the CNS have not been well characterized, in large part due to the lack of availability of a CNS-penetrant sGC stimulator. Recently, we described the first CNS-penetrant sGC stimulator in clinical development and its ability to improve neuronal activity, mediate neuroprotection, and increase cognitive performance in nonclinical models [ 9 ]. Although the impact of sGC stimulation on neuroinflammation remains to be determined, cGMP signaling has been implicated in inflammatory response modulation in the CNS.…”