5mhp
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==Novel Imidazo[1,2-a]pyridine Derivatives with Potent Autotaxin/ENPP2 Inhibitor Activity== | |
| + | <StructureSection load='5mhp' size='340' side='right' caption='[[5mhp]], [[Resolution|resolution]] 2.43Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[5mhp]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MHP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5MHP FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7NB:2-[[2-ethyl-8-methyl-6-[4-[2-(3-oxidanylazetidin-1-yl)-2-oxidanylidene-ethyl]piperazin-1-yl]imidazo[1,2-a]pyridin-3-yl]-methyl-amino]-4-(4-fluorophenyl)-1,3-thiazole-5-carbonitrile'>7NB</scene>, <scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=SCN:THIOCYANATE+ION'>SCN</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | ||
| + | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Alkylglycerophosphoethanolamine_phosphodiesterase Alkylglycerophosphoethanolamine phosphodiesterase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.4.39 3.1.4.39] </span></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=5mhp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mhp OCA], [http://pdbe.org/5mhp PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5mhp RCSB], [http://www.ebi.ac.uk/pdbsum/5mhp PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5mhp ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/ENPP2_HUMAN ENPP2_HUMAN]] Hydrolyzes lysophospholipids to produce lysophosphatidic acid (LPA) in extracellular fluids. Major substrate is lysophosphatidylcholine. Also can act on sphingosylphosphphorylcholine producing sphingosine-1-phosphate, a modulator of cell motility. Can hydrolyze, in vitro, bis-pNPP, to some extent pNP-TMP, and barely ATP. Involved in several motility-related processes such as angiogenesis and neurite outgrowth. Acts as an angiogenic factor by stimulating migration of smooth muscle cells and microtubule formation. Stimulates migration of melanoma cells, probably via a pertussis toxin-sensitive G protein. May have a role in induction of parturition. Possible involvement in cell proliferation and adipose tissue development. Tumor cell motility-stimulating factor.<ref>PMID:11559573</ref> <ref>PMID:1733949</ref> <ref>PMID:21240271</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Autotaxin is a circulating enzyme with a major role in the production of lysophosphatic acid (LPA) species in blood. A role for the autotaxin/LPA axis has been suggested in many disease areas including pulmonary fibrosis. Structural modifications of the known autotaxin inhibitor lead compound 1, to attenuate hERG inhibition, remove CYP3A4 time-dependent inhibition, and improve pharmacokinetic properties, led to the identification of clinical candidate GLPG1690 (11). Compound 11 was able to cause a sustained reduction of LPA levels in plasma in vivo and was shown to be efficacious in a bleomycin-induced pulmonary fibrosis model in mice and in reducing extracellular matrix deposition in the lung while also reducing LPA 18:2 content in bronchoalveolar lavage fluid. Compound 11 is currently being evaluated in an exploratory phase 2a study in idiopathic pulmonary fibrosis patients. | ||
| - | + | Discovery of 2-[[2-Ethyl-6-[4-[2-(3-hydroxyazetidin-1-yl)-2-oxoethyl]piperazin-1-yl]-8-methyli midazo[1,2-a]pyridin-3-yl]methylamino]-4-(4-fluorophenyl)thiazole-5-carbonitrile (GLPG1690), a First-in-Class Autotaxin Inhibitor Undergoing Clinical Evaluation for the Treatment of Idiopathic Pulmonary Fibrosis.,Desroy N, Housseman C, Bock X, Joncour A, Bienvenu N, Cherel L, Labeguere V, Rondet E, Peixoto C, Grassot JM, Picolet O, Annoot D, Triballeau N, Monjardet A, Wakselman E, Roncoroni V, Le Tallec S, Blanque R, Cottereaux C, Vandervoort N, Christophe T, Mollat P, Lamers M, Auberval M, Hrvacic B, Ralic J, Oste L, van der Aar E, Brys R, Heckmann B J Med Chem. 2017 May 11;60(9):3580-3590. doi: 10.1021/acs.jmedchem.7b00032. Epub , 2017 May 1. PMID:28414242<ref>PMID:28414242</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| - | [[Category: | + | <div class="pdbe-citations 5mhp" style="background-color:#fffaf0;"></div> |
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Alkylglycerophosphoethanolamine phosphodiesterase]] | ||
[[Category: Fleury, D]] | [[Category: Fleury, D]] | ||
| + | [[Category: Lamers, M]] | ||
| + | [[Category: Mollat, P]] | ||
[[Category: Mueller, I]] | [[Category: Mueller, I]] | ||
[[Category: Triballeau, N]] | [[Category: Triballeau, N]] | ||
[[Category: Vercheval, L]] | [[Category: Vercheval, L]] | ||
| - | [[Category: | + | [[Category: Atx]] |
| + | [[Category: Enpp2]] | ||
| + | [[Category: Hydrolase]] | ||
| + | [[Category: Inhibitor]] | ||
Revision as of 03:54, 30 August 2017
Novel Imidazo[1,2-a]pyridine Derivatives with Potent Autotaxin/ENPP2 Inhibitor Activity
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