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 Johnson; Zhixin 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

doi:10.1021/acs.jmedchem.7b00598

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 Na_V1.7

J Med Chem. 2017 Aug 24;60(16):7029-7042. doi: 10.1021/acs.jmedchem.7b00598. Epub 2017 Aug 10.

Authors

Nigel A Swain, Dave Batchelor, Serge Beaudoin¹, Bruce M Bechle², Paul A Bradley, Alan D Brown, Bruce Brown, Ken J Butcher, Richard P Butt, Mark L Chapman¹, 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 Johnson¹, Zhixin Lin¹, Christopher J Markworth¹, Brian E Marron¹, David S Millan, Shoko Nakagawa, Andy Pike, David Printzenhoff¹, David J Rawson, Sarah J Ransley, Steven M Reister¹, Kosuke Sasaki, R Ian Storer, Paul A Stupple, Christopher W West¹

Affiliations

¹ Icagen Inc. , 4222 Emperor Blvd no. 350, Durham, North Carolina 27703, United States.
² Worldwide Medicinal Chemistry, Pfizer Inc. , Eastern Point Road, Groton, Connecticut 06340, United States.

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

Abstract

A series of acidic diaryl ether heterocyclic sulfonamides that are potent and subtype selective Na_V1.7 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 Na_V1.7 inhibitor clinical candidate PF-05089771 (34) which binds to a site in the voltage sensing domain.

MeSH terms

Cell Line
Cytochrome P-450 CYP2C9 / metabolism
Cytochrome P-450 CYP2C9 Inhibitors / chemical synthesis
Cytochrome P-450 CYP2C9 Inhibitors / chemistry
Cytochrome P-450 CYP2C9 Inhibitors / pharmacokinetics
Cytochrome P-450 CYP2C9 Inhibitors / pharmacology
Cytochrome P-450 CYP3A / metabolism
Cytochrome P-450 CYP3A Inhibitors / chemical synthesis
Cytochrome P-450 CYP3A Inhibitors / chemistry
Cytochrome P-450 CYP3A Inhibitors / pharmacokinetics
Cytochrome P-450 CYP3A Inhibitors / pharmacology
Drug Design
Humans
Microsomes, Liver / metabolism
NAV1.7 Voltage-Gated Sodium Channel / chemistry
NAV1.7 Voltage-Gated Sodium Channel / metabolism*
Phenyl Ethers / chemical synthesis
Phenyl Ethers / chemistry
Phenyl Ethers / pharmacokinetics
Phenyl Ethers / pharmacology*
Structure-Activity Relationship
Sulfonamides / chemical synthesis
Sulfonamides / chemistry
Sulfonamides / pharmacokinetics
Sulfonamides / pharmacology*
Voltage-Gated Sodium Channel Blockers / chemical synthesis
Voltage-Gated Sodium Channel Blockers / chemistry
Voltage-Gated Sodium Channel Blockers / pharmacokinetics
Voltage-Gated Sodium Channel Blockers / pharmacology*

Substances

Cytochrome P-450 CYP2C9 Inhibitors
Cytochrome P-450 CYP3A Inhibitors
NAV1.7 Voltage-Gated Sodium Channel
PF-05089771
Phenyl Ethers
SCN9A protein, human
Sulfonamides
Voltage-Gated Sodium Channel Blockers
CYP2C9 protein, human
Cytochrome P-450 CYP2C9
Cytochrome P-450 CYP3A
CYP3A4 protein, human