Design and Synthesis of Novel and Selective Phosphodiesterase 2 (PDE2a) Inhibitors for the Treatment of Memory Disorders.
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.
Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States.
Laurent
0000-0002-9172-7840
L
Gomez
Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States.
Mark Eben
ME
Massari
Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States.
Troy
T
Vickers
Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States.
Graeme
G
Freestone
Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States.
William
W
Vernier
Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States.
Kiev
K
Ly
Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States.
Rui
R
Xu
Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States.
Margaret
M
McCarrick
Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States.
Tami
T
Marrone
Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States.
Markus
M
Metz
Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States.
Yingzhou G
YG
Yan
Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States.
Zachary W
ZW
Yoder
Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States.
Robert
R
Lemus
Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States.
Nicola J
NJ
Broadbent
Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States.
Richard
R
Barido
Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States.
Noelle
N
Warren
Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States.
Kara
K
Schmelzer
Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States.
David
D
Neul
Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States.
Dong
D
Lee
Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States.
Carsten B
CB
Andersen
Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States.
Kristen
K
Sebring
Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States.
Kathleen
K
Aertgeerts
Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States.
Xianbo
X
Zhou
Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States.
Ali
A
Tabatabaei
Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States.
Marco
M
Peters
Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States.
J Guy
JG
Breitenbucher
D002853:Chromatography, Liquid; D005092:Exonucleases / Q000187:drug effects*; D006801:Humans; D008569:Memory Disorders / Q000188:drug therapy*; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D066244:Proton Magnetic Resonance Spectroscopy
D010726:Phosphodiesterase Inhibitors; D005092:Exonucleases; C022650:spleen exonuclease