RESUMEN
Chemical modulation of a formerly disclosed DGAT-1 inhibitor resulted in the identification of a compound with a suitable profile for preclinical development. Optimisation of solubility is discussed and a PK/PD study is presented.
Asunto(s)
Diacilglicerol O-Acetiltransferasa/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Oxadiazoles/farmacología , Tiadiazoles/farmacología , Diacilglicerol O-Acetiltransferasa/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estructura Molecular , Oxadiazoles/síntesis química , Oxadiazoles/química , Relación Estructura-Actividad , Tiadiazoles/síntesis química , Tiadiazoles/químicaRESUMEN
Starting from 11ß-HSD1 inhibitors that were active ex vivo but with Cyp 3A4 liability, we obtained a new series of adamantane ureas displaying potent inhibition of both human and rodent 11ß-HSD1 enzymes, devoid of Cyp 3A4 interactions, and rationally designed to provide long-lasting inhibition in target tissues. Final optimizations lead to SAR184841 with good oral pharmacokinetic properties showing in vivo activity and improvement of metabolic parameters in a physiopathological model of type 2 diabetes.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Adamantano/farmacología , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Adamantano/química , Adamantano/farmacocinética , Animales , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animales de Enfermedad , Humanos , Ratones , Ratones Transgénicos , Relación Estructura-ActividadRESUMEN
A novel class of DGAT1 inhibitors containing a thiadiazole core has been discovered. Chemical optimization lead to inhibitors of human DGAT1 with an appropriate ADME profile and that show in vivo activity in target tissues.
Asunto(s)
Diacilglicerol O-Acetiltransferasa/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Hipoglucemiantes/síntesis química , Tiadiazoles/síntesis química , Triglicéridos/antagonistas & inhibidores , Células CACO-2 , Ensayos Clínicos como Asunto , Diacilglicerol O-Acetiltransferasa/metabolismo , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Humanos , Hipoglucemiantes/farmacología , Modelos Moleculares , Estereoisomerismo , Relación Estructura-Actividad , Tiadiazoles/farmacología , Triglicéridos/biosíntesisRESUMEN
A High Throughput Screening campaign allowed the identification of a novel class of ureas as 11ß-HSD1 inhibitors. Rational chemical optimization provided potent and selective inhibitors of both human and murine 11ß-HSD1 with an appropriate ADME profile and ex vivo activity in target tissues.