5k7k | pdb_00005k7k

Design and Optimization of Biaryl Ether Aryl Sulfonamides as Selective Inhibitors of NaV1.7: Discovery of Clinical Candidate PF-05089771

spinqualitylabelsall models 5k7k, resolution 2.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5k7k is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 6RJ, HEM Activity: Oxidoreductase, with EC number 1.14.13.80 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [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. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Proteopedia Page Contributors and Editors (what is this?)

OCA