AI Article Synopsis
- PDE2A inhibitors have shown potential in improving cognitive function in preclinical models, sparking interest in their further development.
- Researchers developed a new, highly potent PDE2A inhibitor (PF-05085727) that effectively penetrates the brain and demonstrates significant biochemical changes related to PDE2A inhibition.
- The compound also reverses cognitive impairments caused by NMDA antagonists in rodents, suggesting it could enhance NMDA signaling and holds promise for future clinical applications in cognition.
Article Abstract
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.
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| http://dx.doi.org/10.1021/acs.jmedchem.7b00397 | DOI Listing |
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