RESUMO
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.
Assuntos
Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Éteres Fenílicos/farmacologia , Sulfonamidas/farmacologia , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Linhagem Celular , Citocromo P-450 CYP2C9/metabolismo , Inibidores do Citocromo P-450 CYP2C9/síntese química , Inibidores do Citocromo P-450 CYP2C9/química , Inibidores do Citocromo P-450 CYP2C9/farmacocinética , Inibidores do Citocromo P-450 CYP2C9/farmacologia , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A/síntese química , Inibidores do Citocromo P-450 CYP3A/química , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Inibidores do Citocromo P-450 CYP3A/farmacologia , Desenho de Fármacos , Humanos , Microssomos Hepáticos/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.7/química , Éteres Fenílicos/síntese química , Éteres Fenílicos/química , Éteres Fenílicos/farmacocinética , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/farmacocinética , Bloqueadores do Canal de Sódio Disparado por Voltagem/síntese química , Bloqueadores do Canal de Sódio Disparado por Voltagem/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacocinéticaRESUMO
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.
RESUMO
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.
Assuntos
Dipeptidil Peptidase 4/metabolismo , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Pirrolidinas/química , Pirrolidinas/farmacologia , Valina/análogos & derivados , Administração Oral , Animais , Cães , Inibidores de Proteases/síntese química , Pirrolidinas/síntese química , Ratos , Valina/síntese química , Valina/química , Valina/farmacologiaRESUMO
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.