4ZO5

PDE10 complexed with 4-isopropoxy-2-(2-(3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)isoindoline-1,3-dione

Summary for 4ZO5

• Entry DOI: 10.2210/pdb4zo5/pdb
• Descriptor: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A, ZINC ION, MAGNESIUM ION, ... (6 entities in total)
• Functional Keywords: phosphodiesterase inhibitor, 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: 75873.63

Authors

Yan, Y. (deposition date: 2015-05-06, release date: 2015-08-12, Last modification date: 2023-09-27)

Primary citation

Cox, C.D.,Hostetler, E.D.,Flores, B.A.,Evelhoch, J.L.,Fan, H.,Gantert, L.,Holahan, M.,Eng, W.,Joshi, A.,McGaughey, G.,Meng, X.,Purcell, M.,Raheem, I.T.,Riffel, K.,Yan, Y.,Renger, J.J.,Smith, S.M.,Coleman, P.J.
Discovery of [(11)C]MK-8193 as a PET tracer to measure target engagement of phosphodiesterase 10A (PDE10A) inhibitors.
Bioorg.Med.Chem.Lett., 25:4893-4898, 2015

PubMed Abstract: Phosphodiesterase 10A (PDE10A) inhibition has recently been identified as a potential mechanism to treat multiple symptoms that manifest in schizophrenia. In order to facilitate preclinical development and support key proof-of-concept clinical trials of novel PDE10A inhibitors, it is critical to discover positron emission tomography (PET) tracers that enable plasma concentration/PDE10A occupancy relationships to be established across species with structurally diverse PDE10A inhibitors. In this Letter, we describe how a high-throughput screening hit was optimized to provide [(11)C]MK-8193 (8j), a PET tracer that supports the determination of plasma concentration/PDE10A occupancy relationships for structurally diverse series of PDE10A inhibitors in both rat and rhesus monkey.

PubMed: 26077491
DOI: 10.1016/j.bmcl.2015.05.080

Experimental method

X-RAY DIFFRACTION (2.5 Å)