First Optimization of Novel, Potent, Selective PDE11A4 Inhibitors for Age-Related Cognitive Decline

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.