jm7b00302_si_002.csv (1.23 kB)
Discovery of Selective Phosphodiesterase 1 Inhibitors with Memory Enhancing Properties
dataset
posted on 2017-04-13, 14:19 authored by Brian Dyck, Bryan Branstetter, Tawfik Gharbaoui, Andrew R. Hudson, J. Guy Breitenbucher, Laurent Gomez, Iriny Botrous, Tami Marrone, Richard Barido, Charles K. Allerston, E. Peder Cedervall, Rui Xu, Vandana Sridhar, Ryan Barker, Kathleen Aertgeerts, Kara Schmelzer, David Neul, Dong Lee, Mark Eben Massari, Carsten B. Andersen, Kristen Sebring, Xianbo Zhou, Robert Petroski, James Limberis, Martin Augustin, Lawrence E. Chun, Thomas E. Edwards, Marco Peters, Ali TabatabaeiA series of potent
thienotriazolopyrimidinone-based PDE1 inhibitors
was discovered. X-ray crystal structures of example compounds from
this series in complex with the catalytic domain of PDE1B and PDE10A
were determined, allowing optimization of PDE1B potency and PDE selectivity.
Reduction of hERG affinity led to greater than a 3000-fold selectivity
for PDE1B over hERG. 6-(4-Methoxybenzyl)-9-((tetrahydro-2H-pyran-4-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one was identified as an orally bioavailable and brain
penetrating PDE1B enzyme inhibitor with potent memory-enhancing effects
in a rat model of object recognition memory.
