RESUMO
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.
Assuntos
Diacilglicerol O-Aciltransferase/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Hipoglicemiantes/síntese química , Oxidiazóis/síntese química , Animais , Diabetes Mellitus/tratamento farmacológico , Diacilglicerol O-Aciltransferase/metabolismo , Cães , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Meia-Vida , Ensaios de Triagem em Larga Escala , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Ligantes , Camundongos , Obesidade/tratamento farmacológico , Oxidiazóis/farmacocinética , Relação Quantitativa Estrutura-Atividade , RatosRESUMO
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.
Assuntos
Aminas/química , Aziridinas/síntese química , Aziridinas/química , Estrutura Molecular , EstereoisomerismoRESUMO
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.