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''' | ==Crystal structure of the catalytic domain of PDE10A complexed with highly potent and brain-penetrant PDE10A Inhibitor with 2-oxindole scaffold== | ||
<StructureSection load='5axq' size='340' side='right' caption='[[5axq]], [[Resolution|resolution]] 1.77Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5axq]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5AXQ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5AXQ FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4LK:3-[3-FLUORANYL-4-[5-METHOXY-4-OXIDANYLIDENE-3-(2-PHENYLPYRAZOL-3-YL)PYRIDAZIN-1-YL]PHENYL]-1,3-OXAZOLIDIN-2-ONE'>4LK</scene>, <scene name='pdbligand=4LP:1-(CYCLOPROPYLMETHYL)-4-FLUORANYL-5-[5-METHOXY-4-OXIDANYLIDENE-3-(2-PHENYLPYRAZOL-3-YL)PYRIDAZIN-1-YL]-3,3-DIMETHYL-INDOL-2-ONE'>4LP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5axp|5axp]]</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=5axq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5axq OCA], [http://pdbe.org/5axq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5axq RCSB], [http://www.ebi.ac.uk/pdbsum/5axq PDBsum]</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 == | |||
Highly potent and brain-penetrant phosphodiesterase 10A (PDE10A) inhibitors based on the 2-oxindole scaffold were designed and synthesized. (2-Oxo-1,3-oxazolidin-3-yl)phenyl derivative 1 showed the high P-glycoprotein (P-gp) efflux (efflux ratio (ER)=6.2) despite the potent PDE10A inhibitory activity (IC50=0.94nM). We performed an optimization study to improve both the P-gp efflux ratio and PDE10A inhibitory activity by utilizing structure-based drug design (SBDD) techniques based on the X-ray crystal structure with PDE10A. Finally, 1-(cyclopropylmethyl)-4-fluoro-5-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyr idazin-1(4H)-yl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (19e) was identified with improved P-gp efflux (ER=1.4) and an excellent PDE10A inhibitory activity (IC50=0.080nM). Compound 19e also exhibited satisfactory brain penetration, and suppressed PCP-induced hyperlocomotion with a minimum effective dose of 0.3mg/kg by oral administration in mice. | |||
Design and synthesis of a novel 2-oxindole scaffold as a highly potent and brain-penetrant phosphodiesterase 10A inhibitor.,Yoshikawa M, Kamisaki H, Kunitomo J, Oki H, Kokubo H, Suzuki A, Ikemoto T, Nakashima K, Kamiguchi N, Harada A, Kimura H, Taniguchi T Bioorg Med Chem. 2015 Nov 15;23(22):7138-49. doi: 10.1016/j.bmc.2015.10.002. Epub, 2015 Oct 9. PMID:26494583<ref>PMID:26494583</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 5axq" style="background-color:#fffaf0;"></div> | |||
[[Category: | == References == | ||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Oki, H]] | |||
[[Category: Zama, Y]] | [[Category: Zama, Y]] | ||
[[Category: | [[Category: Hydrolase-hydrolase inhibitor complex]] | ||
[[Category: Hydrolase/hydrolase inhibitor]] | |||
Revision as of 01:16, 1 December 2015
Crystal structure of the catalytic domain of PDE10A complexed with highly potent and brain-penetrant PDE10A Inhibitor with 2-oxindole scaffoldCrystal structure of the catalytic domain of PDE10A complexed with highly potent and brain-penetrant PDE10A Inhibitor with 2-oxindole scaffold
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 PubMedHighly potent and brain-penetrant phosphodiesterase 10A (PDE10A) inhibitors based on the 2-oxindole scaffold were designed and synthesized. (2-Oxo-1,3-oxazolidin-3-yl)phenyl derivative 1 showed the high P-glycoprotein (P-gp) efflux (efflux ratio (ER)=6.2) despite the potent PDE10A inhibitory activity (IC50=0.94nM). We performed an optimization study to improve both the P-gp efflux ratio and PDE10A inhibitory activity by utilizing structure-based drug design (SBDD) techniques based on the X-ray crystal structure with PDE10A. Finally, 1-(cyclopropylmethyl)-4-fluoro-5-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyr idazin-1(4H)-yl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (19e) was identified with improved P-gp efflux (ER=1.4) and an excellent PDE10A inhibitory activity (IC50=0.080nM). Compound 19e also exhibited satisfactory brain penetration, and suppressed PCP-induced hyperlocomotion with a minimum effective dose of 0.3mg/kg by oral administration in mice. Design and synthesis of a novel 2-oxindole scaffold as a highly potent and brain-penetrant phosphodiesterase 10A inhibitor.,Yoshikawa M, Kamisaki H, Kunitomo J, Oki H, Kokubo H, Suzuki A, Ikemoto T, Nakashima K, Kamiguchi N, Harada A, Kimura H, Taniguchi T Bioorg Med Chem. 2015 Nov 15;23(22):7138-49. doi: 10.1016/j.bmc.2015.10.002. Epub, 2015 Oct 9. PMID:26494583[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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