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8di4
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==Discovery of MK-8189, a highly potent and selective PDE10A inhibitor for the treatment of schizophrenia== | |
| + | <StructureSection load='8di4' size='340' side='right'caption='[[8di4]], [[Resolution|resolution]] 2.02Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[8di4]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8DI4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8DI4 FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=S9I:2-methyl-6-{[(1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl]methoxy}-N-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]pyrimidin-4-amine'>S9I</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'>[https://proteopedia.org/fgij/fg.htm?mol=8di4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8di4 OCA], [https://pdbe.org/8di4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8di4 RCSB], [https://www.ebi.ac.uk/pdbsum/8di4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8di4 ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [https://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 == | ||
| + | PDE10A is an important regulator of striatal signaling that, when inhibited, can normalize dysfunctional activity. Given the involvement of dysfunctional striatal activity with schizophrenia, PDE10A inhibition represents a potentially novel means for its treatment. With the goal of developing PDE10A inhibitors, early optimization of a fragment hit through rational design led to a series of potent pyrimidine PDE10A inhibitors that required further improvements in physicochemical properties, off-target activities, and pharmacokinetics. Herein we describe the discovery of an isomeric pyrimidine series that addresses the liabilities seen with earlier compounds and resulted in the invention of compound 18 (MK-8189), which is currently in Phase 2b clinical development for the treatment of schizophrenia. | ||
| - | + | Discovery of MK-8189, a Highly Potent and Selective PDE10A Inhibitor for the Treatment of Schizophrenia.,Layton ME, Kern JC, Hartingh TJ, Shipe WD, Raheem I, Kandebo M, Hayes RP, Huszar S, Eddins D, Ma B, Fuerst J, Wollenberg GK, Li J, Fritzen J, McGaughey GB, Uslaner JM, Smith SM, Coleman PJ, Cox CD J Med Chem. 2023 Jan 26;66(2):1157-1171. doi: 10.1021/acs.jmedchem.2c01521. Epub , 2023 Jan 9. PMID:36624931<ref>PMID:36624931</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: Hayes | + | <div class="pdbe-citations 8di4" style="background-color:#fffaf0;"></div> |
| - | [[Category: Yan | + | == References == |
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Hayes RP]] | ||
| + | [[Category: Yan Y]] | ||
Revision as of 06:46, 8 February 2023
Discovery of MK-8189, a highly potent and selective PDE10A inhibitor for the treatment of schizophrenia
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