Discovery of Selective Phosphodiesterase 1 Inhibitors with Memory Enhancing Properties

• Published in: Journal of medicinal chemistry 2017-04, Vol.60 (8), p.3472-3483
• Main Authors: Dyck, Brian, Branstetter, Bryan, Gharbaoui, Tawfik, Hudson, Andrew R, Breitenbucher, J. Guy, Gomez, Laurent, Botrous, Iriny, Marrone, Tami, Barido, Richard, Allerston, Charles K, Cedervall, E. Peder, Xu, Rui, Sridhar, Vandana, Barker, Ryan, Aertgeerts, Kathleen, Schmelzer, Kara, Neul, David, Lee, Dong, Massari, Mark Eben, Andersen, Carsten B, Sebring, Kristen, Zhou, Xianbo, Petroski, Robert, Limberis, James, Augustin, Martin, Chun, Lawrence E, Edwards, Thomas E, Peters, Marco, Tabatabaei, Ali
• Format: Article
• Language: English
• Subjects: Crystallography, X-Ray; Drug Discovery; Memory - drug effects; Phosphodiesterase Inhibitors - chemistry; Phosphodiesterase Inhibitors - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.7b00302

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.