RESUMO
Diamide compounds were identified as potent DGAT1 inhibitors in vitro, but their poor molecular properties resulted in low oral bioavailability, both systemically and to DGAT1 in the enterocytes of the small intestine, resulting in a lack of efficacy in vivo. Replacing an N-alkyl group on the diamide with an N-aryl group was found to be an effective strategy to confer oral bioavailability and oral efficacy in this lipophilic diamide class of inhibitors.
Assuntos
Diacilglicerol O-Aciltransferase/antagonistas & inibidores , Diamida/química , Inibidores Enzimáticos/química , Animais , Linhagem Celular Tumoral , Diacilglicerol O-Aciltransferase/metabolismo , Diamida/síntese química , Diamida/farmacocinética , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Meia-Vida , Humanos , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Bioisosteric analogues of pachastrissamine that contain sulfur and selenium atoms replacing the oxygen in the ring system, were efficiently prepared from a cyclic sulfate intermediate by sequential intermolecular and intramolecular S(N)2 displacement reactions of the dianions. The analogues exhibited cytotoxicities comparable to that of pachastrissamine.