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Published on: January 11, 2020
First Optimization of Novel, Potent, Selective PDE11A4 Inhibitors for Age-Related Cognitive Decline
Shams Ul Mahmood1,2, Mariana Lozano Gonzalez1,2, Sreedhar Tummalapalli1,2
1Department of Chemistry & Biochemistry, Montclair State University, Montclair, New Jersey 07043, United States.
Insights
Inhibiting phosphodiesterase 11A4 (PDE11A4), found in the memory-forming hippocampus, may combat age-related cognitive decline. PDE11A4 inhibitors show promise for treating memory deficits in aging.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Phosphodiesterase 11A4 (PDE11A4) is a cyclic nucleotide hydrolase uniquely expressed in the hippocampal formation, crucial for long-term memory.
- PDE11A4 expression elevates in the aging hippocampus in both humans and rodents.
- PDE11A knockout mice exhibit no age-related memory deficits or histopathology.
Purpose of the Study:
- To develop potent and selective PDE11A4 inhibitors for potential therapeutic use.
- To investigate the therapeutic potential of PDE11A4 inhibition for age-related cognitive decline.
Main Methods:
- Utilized a yeast-based high-throughput screen to identify initial PDE11A4 inhibitors.
- Optimized lead compounds to enhance potency and pharmaceutical properties.
- Assessed inhibitor potency and selectivity in cell-based assays.
Main Results:
- Achieved a greater than 10-fold increase in inhibitor potency.
- Developed selective, cell-penetrant PDE11A4 inhibitors.
- Identified an inhibitor 10-fold more potent than tadalafil in cell-based activity.
Conclusions:
- PDE11A4 inhibition represents a viable therapeutic strategy for age-related memory decline.
- Optimized PDE11A4 inhibitors demonstrate significant potency and cell permeability.
Abstract:
Phosphodiesterase 11A4 (PDE11A4) is a dual-acting cyclic nucleotide hydrolase expressed in neurons in the CA1, subiculum, amygdalostriatal transition area and amygdalohippocampal area of the extended hippocampal formation. PDE11A4 is the only PDE enzyme to emanate solely from hippocampal formation, a key brain region for the formation of long-term memory. PDE11A4 expression increases in the hippocampal formation of both humans and rodents as they age. Interestingly, PDE11A knockout mice do not show age-related deficits in associative memory and show no gross histopathology. This suggests that inhibition of PDE11A4 might serve as a therapeutic option for age-related cognitive decline. A novel, yeast-based high throughput screen previously identified moderately potent, selective PDE11A4 inhibitors, and this work describes initial efforts that improved potency more than 10-fold and improved some pharmaceutical properties of one of these scaffolds, leading to selective, cell-penetrant PDE11A4 inhibitors, one of which is 10-fold more potent compared to tadalafil in cell-based activity.
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