PDE11A is a dual substrate (cGMP, cAMP) phosphodiesterase strongly expressed in the CNS in neurons in the superficial layer of CA1, the subiculum and regions adjacently anterior to the hippocampus. These brain regions regulate memory, motivation, mood stability and social behaviors. PDE11A proteinopathies develop with age, associated in part with increased expression, and PDE11A knockout mice are resistant to age-related cognitive decline of social associative memories. Importantly, PDE11A KO mice show no noticeable histopathology at 1 year and exhibit normal reproduction and significant off-target activity against PDE11 by tadalafil suggests that PDE11 inhibition is well tolerated. Unlike many other members of this large family of enzymes, PDE11 has not been widely investigated for therapeutic applications and no drug like, selective inhibitors are known. To address this and to provide candidates to evaluate the role of PDE11A in neurobiology and function, a novel, yeast-based high throughput screen identified several distinct scaffolds that demonstrated moderately potent and selective inhibition of PDE11A. This poster will present work in progress with one of these templates that provides the first examples of potent, selective PDE11A inhibitors active in cell models of age-related PDE11A proteinopathies.

PDE11A inhibition for CNS disorders

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ACS Fall 2022

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