1区 · 医学
Article
作者: Lee, Dong ; Zhou, Xianbo ; Yan, Yingzhou G. ; Gomez, Laurent ; Warren, Noelle ; Aertgeerts, Kathleen ; Metz, Markus ; Marrone, Tami ; Vernier, William ; Lemus, Robert ; Broadbent, Nicola J. ; Ly, Kiev ; Freestone, Graeme ; Sebring, Kristen ; Xu, Rui ; Yoder, Zachary W. ; Neul, David ; Barido, Richard ; Breitenbucher, J. Guy ; Tabatabaei, Ali ; Peters, Marco ; McCarrick, Margaret ; Vickers, Troy ; Andersen, Carsten B. ; Massari, Mark Eben ; Schmelzer, Kara
A series of potent and selective [1,2,4]triazolo[1,5-a]pyrimidine PDE2a inhibitors is reported. The design and improvement of the binding properties of this series was achieved using X-ray crystal structures in conjunction with careful analysis of electronic and structural requirements for the PDE2a enzyme. One of the lead compounds, compound 27 (DNS-8254), was identified as a potent and highly selective PDE2a enzyme inhibitor with favorable rat pharmacokinetic properties. Interestingly, the increased potency of compound 27 was facilitated by the formation of a halogen bond with the oxygen of Tyr827 present in the PDE2a active site. In vivo, compound 27 demonstrated significant memory enhancing effects in a rat model of novel object recognition. Taken together, these data suggest that compound 27 may be a useful tool to explore the pharmacology of selective PDE2a inhibition.
