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 series of TRPA1 antagonists is described which has as its core structure an indazole moiety. The physical properties and in vitro DMPK profiles are discussed. Good in vivo exposure was obtained with several analogs, allowing efficacy to be assessed in rodent models of inflammatory pain. Two compounds showed significant activity in these models when administered either systemically or topically. Protein chimeras were constructed to indicate compounds from the series bound in the S5 region of the channel, and a computational docking model was used to propose a binding mode for example compounds.
ABSTRACT
We report the synthesis and biological activity of a series of 2-cyano-4-fluoro-1-thiovalylpyrrolidine inhibitors of DPP-IV. Within this series, compound 19 provided a potent, selective, and orally active DPP-IV inhibitor which demonstrated a very long duration of action in both rat and dog.
Subject(s)
Dipeptidyl Peptidase 4/metabolism , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Valine/analogs & derivatives , Administration, Oral , Animals , Dogs , Protease Inhibitors/chemical synthesis , Pyrrolidines/chemical synthesis , Rats , Valine/chemical synthesis , Valine/chemistry , Valine/pharmacologyABSTRACT
It has been shown that bromodimethylsulfonium bromide, generated in situ by treating dimethyl sulfoxide with aqueous hydrobromic acid, is a milder and more selective reagent for electrophilic aromatic bromination than elemental bromine.
