| Literature DB >> 28406621 |
Brian Dyck1, Bryan Branstetter1, Tawfik Gharbaoui1, Andrew R Hudson1, J Guy Breitenbucher1, Laurent Gomez1, Iriny Botrous1, Tami Marrone1, Richard Barido1, Charles K Allerston1, E Peder Cedervall1, Rui Xu1, Vandana Sridhar1, Ryan Barker1, Kathleen Aertgeerts1, Kara Schmelzer1, David Neul1, Dong Lee1, Mark Eben Massari1, Carsten B Andersen1, Kristen Sebring1, Xianbo Zhou1, Robert Petroski1, James Limberis1, Martin Augustin2, Lawrence E Chun3, Thomas E Edwards3, Marco Peters1, Ali Tabatabaei1.
Abstract
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.Entities:
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Year: 2017 PMID： 28406621 DOI： 10.1021/acs.jmedchem.7b00302
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446