4zo5

PDE10 complexed with 4-isopropoxy-2-(2-(3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)isoindoline-1,3-dionePDE10 complexed with 4-isopropoxy-2-(2-(3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)isoindoline-1,3-dione

Structural highlights

4zo5 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.5Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PDE10_HUMAN Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. Can hydrolyze both cAMP and cGMP, but has higher affinity for cAMP and is more efficient with cAMP as substrate.^[1]

Publication Abstract from PubMed

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 [11C]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.

Discovery of [C]MK-8193 as a PET tracer to measure target engagement of phosphodiesterase 10A (PDE10A) inhibitors.,Cox CD, Hostetler ED, Flores BA, Evelhoch JL, Fan H, Gantert L, Holahan M, Eng W, Joshi A, McGaughey G, Meng X, Purcell M, Raheem IT, Riffel K, Yan Y, Renger JJ, Smith SM, Coleman PJ Bioorg Med Chem Lett. 2015 Jun 1. pii: S0960-894X(15)00554-5. doi:, 10.1016/j.bmcl.2015.05.080. PMID:26077491^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Wang H, Liu Y, Hou J, Zheng M, Robinson H, Ke H. Structural insight into substrate specificity of phosphodiesterase 10. Proc Natl Acad Sci U S A. 2007 Apr 3;104(14):5782-7. Epub 2007 Mar 26. PMID:17389385
↑ Cox CD, Hostetler ED, Flores BA, Evelhoch JL, Fan H, Gantert L, Holahan M, Eng W, Joshi A, McGaughey G, Meng X, Purcell M, Raheem IT, Riffel K, Yan Y, Renger JJ, Smith SM, Coleman PJ. Discovery of [C]MK-8193 as a PET tracer to measure target engagement of phosphodiesterase 10A (PDE10A) inhibitors. Bioorg Med Chem Lett. 2015 Jun 1. pii: S0960-894X(15)00554-5. doi:, 10.1016/j.bmcl.2015.05.080. PMID:26077491 doi:http://dx.doi.org/10.1016/j.bmcl.2015.05.080

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OCA

[1] Wang H, Liu Y, Hou J, Zheng M, Robinson H, Ke H. Structural insight into substrate specificity of phosphodiesterase 10. Proc Natl Acad Sci U S A. 2007 Apr 3;104(14):5782-7. Epub 2007 Mar 26. PMID:17389385

[2] Cox CD, Hostetler ED, Flores BA, Evelhoch JL, Fan H, Gantert L, Holahan M, Eng W, Joshi A, McGaughey G, Meng X, Purcell M, Raheem IT, Riffel K, Yan Y, Renger JJ, Smith SM, Coleman PJ. Discovery of [C]MK-8193 as a PET tracer to measure target engagement of phosphodiesterase 10A (PDE10A) inhibitors. Bioorg Med Chem Lett. 2015 Jun 1. pii: S0960-894X(15)00554-5. doi:, 10.1016/j.bmcl.2015.05.080. PMID:26077491 doi:http://dx.doi.org/10.1016/j.bmcl.2015.05.080

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