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
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
Quinone reductase 2 is a mammalian cytosolic FAD-dependent enzyme, the activity of which is not supported by conventional nicotinamide nucleotides. An endobiotic substrate has never been reported for this enzyme nor a set of molecular tools, such as inhibitors. In the present work, we used the recombinant human enzyme, expressed in CHO cells for the systematic screening of both co-substrates and substrates. The co-substrates survey showed that the natural occurring compound, N-ribosylnicotinamide, was a poor co-substrate. The synthetic N-benzylnicotinamide is a better one compared to any other compounds tested. We found that tetrahydrofolic acid acted as a co-substrate for the reduction of menadione catalysed by quinone reductase 2, although with poor potency (Km approximately 2 mM). Among a series of commercially available quinones, a single one was found to be substrate of quinone reductase 2, in the presence of N-benzyldihydronicotinamide: coenzyme Q0. Finally, we tested a series of 197 flavonoids as potential inhibitors. We found apigenin, genistein or kaempferol as good inhibitor of quinone reductase 2 activity with IC50 in the 100 nM range. These compounds, co-substrate, substrate and inhibitors will permit to better know this enzyme, the role of which is still poorly understood.