Application of Structure-Based Design and Parallel Chemistry to Identify a Potent, Selective, and Brain Penetrant Phosphodiesterase 2A Inhibitor

Phosphodiesterase 2A (PDE2A) inhibitors
have been reported to demonstrate
in vivo activity in preclinical models of cognition. To more fully
explore the biology of PDE2A inhibition, we sought to identify potent
PDE2A inhibitors with improved brain penetration as compared to current
literature compounds. Applying estimated human dose calculations while
simultaneously leveraging synthetically enabled chemistry and structure-based
drug design has resulted in a highly potent, selective, brain penetrant
compound 71 (PF-05085727) that effects in vivo biochemical
changes commensurate with PDE2A inhibition along with behavioral and
electrophysiological reversal of the effects of NMDA antagonists in
rodents. This data supports the ability of PDE2A inhibitors to potentiate
NMDA signaling and their further development for clinical cognition
indications.