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| | ==Synthesis and biological evaluation of new triazolo and imidazolopyridine RORgt inverse agonists== | | ==Synthesis and biological evaluation of new triazolo and imidazolopyridine RORgt inverse agonists== |
| - | <StructureSection load='5m96' size='340' side='right' caption='[[5m96]], [[Resolution|resolution]] 1.77Å' scene=''> | + | <StructureSection load='5m96' size='340' side='right'caption='[[5m96]], [[Resolution|resolution]] 1.77Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5m96]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5M96 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5M96 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5m96]] 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=5M96 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5M96 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=Q6Y:~{N}-[8-[[(3~{S})-4-CYCLOPENTYLCARBONYL-3-METHYL-PIPERAZIN-1-YL]METHYL]-7-METHYL-IMIDAZO[1,2-A]PYRIDIN-6-YL]-2-METHYL-PYRIMIDINE-5-CARBOXAMIDE'>Q6Y</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.77Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">RORC, NR1F3, RORG, RZRG ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=Q6Y:~{N}-[8-[[(3~{S})-4-CYCLOPENTYLCARBONYL-3-METHYL-PIPERAZIN-1-YL]METHYL]-7-METHYL-IMIDAZO[1,2-A]PYRIDIN-6-YL]-2-METHYL-PYRIMIDINE-5-CARBOXAMIDE'>Q6Y</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=5m96 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5m96 OCA], [http://pdbe.org/5m96 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5m96 RCSB], [http://www.ebi.ac.uk/pdbsum/5m96 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5m96 ProSAT]</span></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=5m96 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5m96 OCA], [https://pdbe.org/5m96 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5m96 RCSB], [https://www.ebi.ac.uk/pdbsum/5m96 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5m96 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/RORG_HUMAN RORG_HUMAN]] Possible nuclear receptor for hydroxycholesterols, the binding of which strongly promotes coactivators recruitment. Essential for thymopoiesis and the development of several secondary lymphoid tissues, including lymph nodes. Involved in lineage specification of uncommitted CD4(+) T-helper cells into Th17 cells. Regulate the expression of several components of the circadian clock. | + | [https://www.uniprot.org/uniprot/RORG_HUMAN RORG_HUMAN] Possible nuclear receptor for hydroxycholesterols, the binding of which strongly promotes coactivators recruitment. Essential for thymopoiesis and the development of several secondary lymphoid tissues, including lymph nodes. Involved in lineage specification of uncommitted CD4(+) T-helper cells into Th17 cells. Regulate the expression of several components of the circadian clock. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Kallen, J]] | + | [[Category: Large Structures]] |
| - | [[Category: Inverse agonist]] | + | [[Category: Kallen J]] |
| - | [[Category: Ligand-binding domain]]
| + | |
| - | [[Category: Nuclear hormone receptor]]
| + | |
| - | [[Category: Transcription]]
| + | |
| Structural highlights
Function
RORG_HUMAN Possible nuclear receptor for hydroxycholesterols, the binding of which strongly promotes coactivators recruitment. Essential for thymopoiesis and the development of several secondary lymphoid tissues, including lymph nodes. Involved in lineage specification of uncommitted CD4(+) T-helper cells into Th17 cells. Regulate the expression of several components of the circadian clock.
Publication Abstract from PubMed
Retinoic-acid-related orphan receptor gammat (RORgammat) is a key transcription factor implicated in the production of pro-inflammatory Th17 cytokines, which drive a number of autoimmune diseases. Despite diverse chemical series having been reported, combining high potency with a good physicochemical profile has been a very challenging task in the RORgammat inhibitor field. Based on available chemical structures and incorporating in-house knowledge, a new series of triazolo- and imidazopyridine RORgammat inverse agonists was designed. In addition, replacement of the terminal cyclopentylamide metabolic soft spot by five-membered heterocycles was investigated. From our efforts, we identified an optimal 6,7,8-substituted imidazo[1,2-a]pyridine core system and a 5-tert-butyl-1,2,4-oxadiazole as cyclopentylamide replacement leading to compounds 10 ((S)-N-(8-((4-(cyclopentanecarbonyl)-3-methylpiperazin-1-yl)methyl)-7-methylimida zo[1,2-a]pyridin-6-yl)-2-methylpyrimidine-5-carboxamide) and 33 ((S)-N-(8-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)-3-methylpiperazin-1-yl)methyl )-7-methylimidazo[1,2-a]pyridin-6-yl)-2-methylpyrimidine-5-carboxamide). Both derivatives showed good pharmacological potencies in biochemical and cell-based assays combined with excellent physicochemical properties, including low to medium plasma protein binding across species. Finally, 10 and 33 were shown to be active in a rodent pharmacokinetic/pharmacodynamic (PK/PD) model after oral gavage at 15 mg kg-1 , lowering IL-17 cytokine production in ex vivo antigen recall assays.
Synthesis and Biological Evaluation of New Triazolo- and Imidazolopyridine RORgammat Inverse Agonists.,Hintermann S, Guntermann C, Mattes H, Carcache DA, Wagner J, Vulpetti A, Billich A, Dawson J, Kaupmann K, Kallen J, Stringer R, Orain D ChemMedChem. 2016 Nov 30. doi: 10.1002/cmdc.201600500. PMID:27902884[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Hintermann S, Guntermann C, Mattes H, Carcache DA, Wagner J, Vulpetti A, Billich A, Dawson J, Kaupmann K, Kallen J, Stringer R, Orain D. Synthesis and Biological Evaluation of New Triazolo- and Imidazolopyridine RORgammat Inverse Agonists. ChemMedChem. 2016 Nov 30. doi: 10.1002/cmdc.201600500. PMID:27902884 doi:http://dx.doi.org/10.1002/cmdc.201600500
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