5k7k
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==Design and Optimization of Biaryl Ether Aryl Sulfonamides as Selective Inhibitors of NaV1.7: Discovery of Clinical Candidate PF-05089771== | |
| + | <StructureSection load='5k7k' size='340' side='right' caption='[[5k7k]], [[Resolution|resolution]] 2.30Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[5k7k]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5K7K OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5K7K FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6RJ:4-[4-chloranyl-2-(1~{H}-pyrazol-4-yl)phenoxy]-3-cyano-~{N}-(1,3-thiazol-2-yl)benzenesulfonamide'>6RJ</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene></td></tr> | ||
| + | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Oxidoreductase Oxidoreductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.13.80 1.14.13.80] </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=5k7k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5k7k OCA], [http://pdbe.org/5k7k PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5k7k RCSB], [http://www.ebi.ac.uk/pdbsum/5k7k PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5k7k ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/CP2C9_HUMAN CP2C9_HUMAN]] Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenytoin, tolbutamide and losartan. | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | A series of acidic diaryl ether heterocyclic sulfonamides that are potent and subtype selective NaV1.7 inhibitors is described. Optimization of early lead matter focused on removal of structural alerts, improving metabolic stability and reducing cytochrome P450 inhibition driven drug-drug interaction concerns to deliver the desired balance of preclinical in vitro properties. Concerns over nonmetabolic routes of clearance, variable clearance in preclinical species, and subsequent low confidence human pharmacokinetic predictions led to the decision to conduct a human microdose study to determine clinical pharmacokinetics. The design strategies and results from preclinical PK and clinical human microdose PK data are described leading to the discovery of the first subtype selective NaV1.7 inhibitor clinical candidate PF-05089771 (34) which binds to a site in the voltage sensing domain. | ||
| - | + | Discovery of Clinical Candidate 4-[2-(5-Amino-1H-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-1,3-thiazol-4 -ylbenzenesulfonamide (PF-05089771): Design and Optimization of Diaryl Ether Aryl Sulfonamides as Selective Inhibitors of NaV1.7.,Swain NA, Batchelor D, Beaudoin S, Bechle BM, Bradley PA, Brown AD, Brown B, Butcher KJ, Butt RP, Chapman ML, Denton S, Ellis D, Galan SRG, Gaulier SM, Greener BS, de Groot MJ, Glossop MS, Gurrell IK, Hannam J, Johnson MS, Lin Z, Markworth CJ, Marron BE, Millan DS, Nakagawa S, Pike A, Printzenhoff D, Rawson DJ, Ransley SJ, Reister SM, Sasaki K, Storer RI, Stupple PA, West CW J Med Chem. 2017 Aug 24;60(16):7029-7042. doi: 10.1021/acs.jmedchem.7b00598. Epub, 2017 Aug 10. PMID:28682065<ref>PMID:28682065</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 5k7k" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Oxidoreductase]] | ||
[[Category: Chrencik, J]] | [[Category: Chrencik, J]] | ||
[[Category: Swain, N]] | [[Category: Swain, N]] | ||
| + | [[Category: Cyp2c9]] | ||
Revision as of 04:16, 30 August 2017
Design and Optimization of Biaryl Ether Aryl Sulfonamides as Selective Inhibitors of NaV1.7: Discovery of Clinical Candidate PF-05089771
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