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.
Subject(s)
NAV1.7 Voltage-Gated Sodium Channel/metabolism , Phenyl Ethers/pharmacology , Sulfonamides/pharmacology , Voltage-Gated Sodium Channel Blockers/pharmacology , 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 , Phenyl Ethers/chemical synthesis , Phenyl Ethers/chemistry , Phenyl Ethers/pharmacokinetics , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Sulfonamides/pharmacokinetics , Voltage-Gated Sodium Channel Blockers/chemical synthesis , Voltage-Gated Sodium Channel Blockers/chemistry , Voltage-Gated Sodium Channel Blockers/pharmacokineticsABSTRACT
A number of libraries were produced to explore the potential of 2,4-diaminopyridine lead 1. The resulting diaminopyridines proved to be potent and selective delta-opioid receptor agonists. Several rounds of lead optimisation using library chemistry identified compound 17 which went on to show efficacy in an electromyography model of neuropathic pain. The structure-activity relationship of the series against the hERG ion channel proved to be a key selectivity hurdle for the series.
