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.
Highlights
Neurodegenerative diseases exact an immense toll on the lives of patients, their families, and healthcare systems across the world
While these calculations do not represent the equilibrium at the steady state, CY6463 can be considered as being a fully central nervous system (CNS) penetrant soluble guanylate cyclase (sGC) stimulator, and vericiguat to have limited exposure in the CNS
At 6 h postdose, there was a significant treatment effect (H (3) 15.1, p 0.005) when rats administered 10 mg/kg CY6463 (p 0.004), but not 3 mg/kg CY6463 (p 0.3883), had higher levels of cerebrospinal fluid (CSF) cyclic guanosine monophosphate (cGMP) vs. vehicletreated rats
Summary
Neurodegenerative diseases exact an immense toll on the lives of patients, their families, and healthcare systems across the world. In light of recent high-profile failures in Alzheimer’s disease (AD) clinical trials (Elmaleh et al, 2019), approaches addressing the broader aspects of neurodegenerative pathologies such as neuroinflammation, synaptic and neuronal dysfunction, and cerebrovascular dysregulation may provide a path forward for new therapies. Intracellular cGMP regulates vascular tone and regional blood flow, fibrosis, and inflammation and has been implicated in neuronal survival and function (Aissa et al, 2016; Garthwaite, 2019). Endothelial cell loss and NO dysregulation are recognized as major contributing factors in neurodegenerative diseases, resulting in reduced blood flow, vascular leakage, and inflammation, along with synaptic dysfunction and neuronal loss (Toth et al, 2017)
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