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

Autor:	Gomez L; Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States., Massari ME; Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States., Vickers T; Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States., Freestone G; Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States., Vernier W; Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States., Ly K; Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States., Xu R; Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States., McCarrick M; Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States., Marrone T; Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States., Metz M; Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States., Yan YG; Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States., Yoder ZW; Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States., Lemus R; Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States., Broadbent NJ; Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States., Barido R; Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States., Warren N; Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States., Schmelzer K; Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States., Neul D; Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States., Lee D; Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States., Andersen CB; Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States., Sebring K; Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States., Aertgeerts K; Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States., Zhou X; Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States., Tabatabaei A; Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States., Peters M; Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States., Breitenbucher JG; Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2017 Mar 09; Vol. 60 (5), pp. 2037-2051. Date of Electronic Publication: 2017 Feb 21.
DOI:	10.1021/acs.jmedchem.6b01793
Abstrakt:	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.
Databáze:	MEDLINE
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