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

Nigel A. Swain, Dave Batchelor, Serge Beaudoin, Bruce M. Bechle, Paul A. Bradley, Alan D. Brown, Bruce Brown, Ken J. Butcher, Richard P. Butt, Mark L. Chapman, Stephen Denton, David Ellis, Sebastien R.G. Galan, Steven M. Gaulier, Ben S. Greener, Marcel J. De Groot, Mel S. Glossop, Ian K. Gurrell, Jo Hannam, Matthew S. JohnsonZhixin Lin, Christopher J. Markworth, Brian E. Marron, David S. Millan, Shoko Nakagawa, Andy Pike, David Printzenhoff, David J. Rawson, Sarah J. Ransley, Steven M. Reister, Kosuke Sasaki, R. Ian Storer, Paul A. Stupple, Christopher W. West

Research output: Contribution to journalArticleResearchpeer-review

39 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)7029-7042
Number of pages14
JournalJournal of Medicinal Chemistry
Volume60
Issue number16
DOIs
Publication statusPublished - 24 Aug 2017
Externally publishedYes

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