2. Academic Validation
  3. Design and Synthesis of Novel and Selective Phosphodiesterase 2 (PDE2a) Inhibitors for the Treatment of Memory Disorders

Design and Synthesis of Novel and Selective Phosphodiesterase 2 (PDE2a) Inhibitors for the Treatment of Memory Disorders

  • J Med Chem. 2017 Mar 9;60(5):2037-2051. doi: 10.1021/acs.jmedchem.6b01793.
Laurent Gomez 1,  Mark Eben Massari 1,  Troy Vickers 1,  Graeme Freestone 1,  William Vernier 1,  Kiev Ly 1,  Rui Xu 1,  Margaret McCarrick 1,  Tami Marrone 1,  Markus Metz 1,  Yingzhou G Yan 1,  Zachary W Yoder 1,  Robert Lemus 1,  Nicola J Broadbent 1,  Richard Barido 1,  Noelle Warren 1,  Kara Schmelzer 1,  David Neul 1,  Dong Lee 1,  Carsten B Andersen 1,  Kristen Sebring 1,  Kathleen Aertgeerts 1,  Xianbo Zhou 1,  Ali Tabatabaei 1,  Marco Peters 1,  J Guy Breitenbucher 1
Affiliations

Affiliation

  • 1 Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States.
PMID: 28165743 DOI: 10.1021/acs.jmedchem.6b01793
Abstract

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.

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