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
  • 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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