RESUMEN
For a series of beta-homophenylalanine based inhibitors of dipeptidyl peptidase IV ADME properties were improved by the incorporation of amide replacements. These efforts led to a novel series of potent and selective inhibitors of DPP-4 that exhibit an attractive pharmacokinetic profile and show excellent efficacy in an animal model of diabetes.
Asunto(s)
Amidas/química , Aminobutiratos/química , Inhibidores de la Dipeptidil-Peptidasa IV , Relación Estructura-Actividad , Amidas/antagonistas & inhibidores , Células CACO-2 , Línea Celular Tumoral , Química Farmacéutica , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Diseño de Fármacos , Humanos , Hipoglucemiantes/antagonistas & inhibidores , Hipoglucemiantes/uso terapéutico , Inhibidores de Proteasas/farmacocinética , Inhibidores de Proteasas/farmacología , Canales de Sodio/metabolismoRESUMEN
A series of highly potent and selective inhibitors of DPP-4 was optimized for ADMET properties. The effort resulted in the discovery of inhibitor 1g, that exhibits excellent efficacy in an oral glucose tolerance test and an attractive pharmacokinetic profile.
Asunto(s)
Aminobutiratos/química , Inhibidores de la Dipeptidil-Peptidasa IV , Hidrocarburos Fluorados/química , Hipoglucemiantes/química , Inhibidores de Proteasas/química , Pirrolidinas/química , Administración Oral , Aminobutiratos/síntesis química , Aminobutiratos/farmacocinética , Animales , Células CACO-2 , Línea Celular Tumoral , Dipeptidil Peptidasa 4/metabolismo , Perros , Humanos , Hidrocarburos Fluorados/síntesis química , Hidrocarburos Fluorados/farmacología , Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacocinética , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacocinética , Pirrolidinas/síntesis química , Pirrolidinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
Modifications of DPP-4 inhibitor 5, that was discovered by structure based design, are described and structure-activity relationships discussed. With analogue 7k one of the most potent non-covalent inhibitors of DPP-4 reported to date (IC(50)=0.38nM) was discovered. X-ray structure of inhibitor 7k bound to DPP-4 revealed a hydrogen bonding interaction with Q553. First successful efforts in balancing overall properties, as demonstrated by improved metabolic stability, highlight the potential of this series.
Asunto(s)
Amidas/síntesis química , Aminobutiratos/química , Inhibidores de la Dipeptidil-Peptidasa IV , Inhibidores de la Dipeptidil-Peptidasa IV/síntesis química , Microsomas Hepáticos/efectos de los fármacos , Sulfonamidas/síntesis química , Amidas/farmacología , Animales , Química Farmacéutica/métodos , Cristalografía por Rayos X/métodos , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Diseño de Fármacos , Péptido 1 Similar al Glucagón/antagonistas & inhibidores , Enlace de Hidrógeno , Concentración 50 Inhibidora , Microsomas Hepáticos/metabolismo , Ratas , Relación Estructura-Actividad , Sulfonamidas/farmacologíaRESUMEN
The co-crystal structure of beta-phenethylamine fragment inhibitor 5 bound to DPP-IV revealed that the phenyl ring occupied the proline pocket of the enzyme. This finding provided the basis for a general hypothesis of a reverse binding mode for beta-phenethylamine-based DPP-IV inhibitors. Novel inhibitor design concepts that obviate substrate-like structure-activity relationships (SAR) were thereby enabled, and novel, potent inhibitors were discovered.