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==Novel, potent, selective and brain penetrant phosphodiesterase 10A inhibitors== | |||
<StructureSection load='6msc' size='340' side='right' caption='[[6msc]], [[Resolution|resolution]] 2.36Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6msc]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6MSC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6MSC FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=JY7:8-fluoro-6-methoxy-3-methyl-1-(3-methylpyridin-4-yl)-3H-pyrazolo[3,4-c]cinnoline'>JY7</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6msc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6msc OCA], [http://pdbe.org/6msc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6msc RCSB], [http://www.ebi.ac.uk/pdbsum/6msc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6msc ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/PDE10_HUMAN 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.<ref>PMID:17389385</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Herein we report the discovery of a novel series of phosphodiesterase 10A inhibitors. Optimization of a HTS hit (17) resulted in potent, selective, and brain penetrant 23 and 26; both exhibited much lower clearance in vivo and decreased volume of distribution (rat PK) and have thus the potential to inhibit the PDE10A target in vivo at a lower efficacious dose than the reference compound WEB-3. | |||
Novel, potent, selective, and brain penetrant phosphodiesterase 10A inhibitors.,Geneste H, Drescher K, Jakob C, Laplanche L, Ochse M, Torrent M Bioorg Med Chem Lett. 2018 Dec 19. pii: S0960-894X(18)30976-4. doi:, 10.1016/j.bmcl.2018.12.029. PMID:30587449<ref>PMID:30587449</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6msc" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Jakob, C G]] | |||
[[Category: Hydrolase]] | |||
[[Category: Phosphodiesterase]] | |||
Revision as of 09:40, 9 January 2019
Novel, potent, selective and brain penetrant phosphodiesterase 10A inhibitorsNovel, potent, selective and brain penetrant phosphodiesterase 10A inhibitors
Structural highlights
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 PubMedHerein we report the discovery of a novel series of phosphodiesterase 10A inhibitors. Optimization of a HTS hit (17) resulted in potent, selective, and brain penetrant 23 and 26; both exhibited much lower clearance in vivo and decreased volume of distribution (rat PK) and have thus the potential to inhibit the PDE10A target in vivo at a lower efficacious dose than the reference compound WEB-3. Novel, potent, selective, and brain penetrant phosphodiesterase 10A inhibitors.,Geneste H, Drescher K, Jakob C, Laplanche L, Ochse M, Torrent M Bioorg Med Chem Lett. 2018 Dec 19. pii: S0960-894X(18)30976-4. doi:, 10.1016/j.bmcl.2018.12.029. PMID:30587449[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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