5UWF

Crystal structure of human PDE10A in complex with inhibitor 16d

Summary for 5UWF

• Entry DOI: 10.2210/pdb5uwf/pdb
• Descriptor: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A, 9-[(1S)-2,2-difluorocyclopropane-1-carbonyl]-6-[(4-methoxyphenyl)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, ZINC ION, ... (5 entities in total)
• Functional Keywords: phosphodiesterase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: Q9Y233
• Total number of polymer chains: 2
• Total formula weight: 80087.01

Authors

Xu, R.,Cedervall, E.P.,Sridhar, V.,Barker, R.,Aertgeerts, K. (deposition date: 2017-02-21, release date: 2017-04-26, Last modification date: 2023-10-04)

Primary citation

Dyck, B.,Branstetter, B.,Gharbaoui, T.,Hudson, A.R.,Breitenbucher, J.G.,Gomez, L.,Botrous, I.,Marrone, T.,Barido, R.,Allerston, C.K.,Cedervall, E.P.,Xu, R.,Sridhar, V.,Barker, R.,Aertgeerts, K.,Schmelzer, K.,Neul, D.,Lee, D.,Massari, M.E.,Andersen, C.B.,Sebring, K.,Zhou, X.,Petroski, R.,Limberis, J.,Augustin, M.,Chun, L.E.,Edwards, T.E.,Peters, M.,Tabatabaei, A.
Discovery of Selective Phosphodiesterase 1 Inhibitors with Memory Enhancing Properties.
J. Med. Chem., 60:3472-3483, 2017

PubMed 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.

PubMed: 28406621
DOI: 10.1021/acs.jmedchem.7b00302

Experimental method

X-RAY DIFFRACTION (1.87 Å)