5u7l
PDE2 catalytic domain complexed with inhibitors
Structural highlights
FunctionPDE2A_HUMAN Cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes.[1] [2] Publication Abstract from PubMedPhosphodiesterase 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. Application of Structure-Based Design and Parallel Chemistry to Identify a Potent, Selective, and Brain Penetrant Phosphodiesterase 2A Inhibitor.,Helal CJ, Arnold EP, Boyden TL, Chang C, Chappie TA, Fennell KF, Forman MD, Hajos M, Harms JF, Hoffman WE, Humphrey JM, Kang Z, Kleiman RJ, Kormos BL, Lee CW, Lu J, Maklad N, McDowell L, Mente S, O'Connor RE, Pandit J, Piotrowski M, Schmidt AW, Schmidt CJ, Ueno H, Verhoest PR, Yang EX J Med Chem. 2017 Jul 13;60(13):5673-5698. doi: 10.1021/acs.jmedchem.7b00397. Epub, 2017 Jun 16. PMID:28574706[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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