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