5K7K

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

Summary for 5K7K

• Entry DOI: 10.2210/pdb5k7k/pdb
• Descriptor: Cytochrome P450 2C9, PROTOPORPHYRIN IX CONTAINING FE, 4-[4-chloranyl-2-(1~{H}-pyrazol-4-yl)phenoxy]-3-cyano-~{N}-(1,3-thiazol-2-yl)benzenesulfonamide, ... (4 entities in total)
• Functional Keywords: cyp2c9, oxidoreductase
• Biological source: Homo sapiens (Human)
• Cellular location: Endoplasmic reticulum membrane; Peripheral membrane protein: P11712
• Total number of polymer chains: 1
• Total formula weight: 55397.29

Authors

Swain, N.,Chrencik, J. (deposition date: 2016-05-26, release date: 2017-06-07, Last modification date: 2023-09-27)

Primary citation

Swain, N.A.,Batchelor, D.,Beaudoin, S.,Bechle, B.M.,Bradley, P.A.,Brown, A.D.,Brown, B.,Butcher, K.J.,Butt, R.P.,Chapman, M.L.,Denton, S.,Ellis, D.,Galan, S.R.G.,Gaulier, S.M.,Greener, B.S.,de Groot, M.J.,Glossop, M.S.,Gurrell, I.K.,Hannam, J.,Johnson, M.S.,Lin, Z.,Markworth, C.J.,Marron, B.E.,Millan, D.S.,Nakagawa, S.,Pike, A.,Printzenhoff, D.,Rawson, D.J.,Ransley, S.J.,Reister, S.M.,Sasaki, K.,Storer, R.I.,Stupple, P.A.,West, C.W.
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.
J. Med. Chem., 60:7029-7042, 2017

PubMed Abstract: A series of acidic diaryl ether heterocyclic sulfonamides that are potent and subtype selective Na1.7 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 Na1.7 inhibitor clinical candidate PF-05089771 (34) which binds to a site in the voltage sensing domain.

PubMed: 28682065
DOI: 10.1021/acs.jmedchem.7b00598

Experimental method

X-RAY DIFFRACTION (2.3 Å)