RESUMEN
A novel series of DGAT-1 inhibitors was discovered from an oxadiazole amide high throughput screening (HTS) hit. Optimisation of potency and ligand lipophilicity efficiency (LLE) resulted in a carboxylic acid containing clinical candidate 53 (AZD3988), which demonstrated excellent DGAT-1 potency (0.6 nM), good pharmacokinetics and pre-clinical in vivo efficacy that could be rationalised through a PK/PD relationship.
Asunto(s)
Diacilglicerol O-Acetiltransferasa/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Hipoglucemiantes/síntesis química , Oxadiazoles/síntesis química , Animales , Diabetes Mellitus/tratamiento farmacológico , Diacilglicerol O-Acetiltransferasa/metabolismo , Perros , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Semivida , Ensayos Analíticos de Alto Rendimiento , Humanos , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Ligandos , Ratones , Obesidad/tratamiento farmacológico , Oxadiazoles/farmacocinética , Relación Estructura-Actividad Cuantitativa , RatasRESUMEN
N-Unsubstituted vinyl aziridines were synthesized via an amine-promoted regioselective nucleophilic aziridination of alpha,beta,gamma,delta-unsaturated carbonyl compounds. The reaction is completely regioselective (>95: 5) for the alpha,beta-alkene and completely diastereoselective, affording the trans-vinyl aziridine in moderate-to-good yields.
Asunto(s)
Aminas/química , Aziridinas/síntesis química , Aziridinas/química , Estructura Molecular , EstereoisomerismoRESUMEN
Cinchona alkaloid-catalyzed reaction of ethyl glyoxylate with substituted ketenes, formed in situ, gives disubstituted beta-lactones in moderate yield and high enantiomeric excess. Subsequent azide ring opening, reduction, and ester hydrolysis allows access to chiral beta-alkyl aspartates.