RESUMEN
The SAR of a series of novel pyrido[3,4-d]pyramid-4-ylamine mGluR1 antagonists is described. The multiple of the unbound K(i) in cerebrospinal fluid necessary to give morphine like analgesic effects in an electromyograph pinch model in rodents is determined and the effect of structure on CNS penetration examined.
Asunto(s)
Antagonistas de Aminoácidos Excitadores/síntesis química , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Animales , Electromiografía/métodos , Antagonistas de Aminoácidos Excitadores/química , Antagonistas de Aminoácidos Excitadores/farmacología , Dimensión del Dolor/efectos de los fármacos , Dimensión del Dolor/métodos , Ratas , Receptores de Glutamato Metabotrópico/fisiología , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Canal de Sodio Activado por Voltaje NAV1.7/metabolismo , Éteres Fenílicos/farmacología , Sulfonamidas/farmacología , Bloqueadores del Canal de Sodio Activado por Voltaje/farmacología , Línea Celular , Citocromo P-450 CYP2C9/metabolismo , Inhibidores del Citocromo P-450 CYP2C9/síntesis química , Inhibidores del Citocromo P-450 CYP2C9/química , Inhibidores del Citocromo P-450 CYP2C9/farmacocinética , Inhibidores del Citocromo P-450 CYP2C9/farmacología , Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A/síntesis química , Inhibidores del Citocromo P-450 CYP3A/química , Inhibidores del Citocromo P-450 CYP3A/farmacocinética , Inhibidores del Citocromo P-450 CYP3A/farmacología , Diseño de Fármacos , Humanos , Microsomas Hepáticos/metabolismo , Canal de Sodio Activado por Voltaje NAV1.7/química , Éteres Fenílicos/síntesis química , Éteres Fenílicos/química , Éteres Fenílicos/farmacocinética , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/química , Sulfonamidas/farmacocinética , Bloqueadores del Canal de Sodio Activado por Voltaje/síntesis química , Bloqueadores del Canal de Sodio Activado por Voltaje/química , Bloqueadores del Canal de Sodio Activado por Voltaje/farmacocinéticaRESUMEN
A series of novel mGluR1 antagonists have been prepared. Incorporation of fragments derived from weak lead matter into a library led to enhanced potency in a new chemical series. A chemistry driven second library iteration, covering a greatly enhanced area of chemical space, maintained good potency and introduced metabolic stability.