Discovery of Selective Phosphodiesterase 1 Inhibitors with Memory Enhancing Properties
journal contributionposted 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 Tabatabaei
A 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.