Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 60, Issue 16, Pages 7029-7042Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.7b00598
Keywords
-
Categories
Ask authors/readers for more resources
A series of acidic diaryl ether heterocyclic sulfonamides that are potent and subtype selective Na(V)1.7 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(V)1.7 inhibitor clinical candidate PF-05089771 (34) which binds to a site in the voltage sensing domain.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available