RESUMO
In the present article, we have reported the design, synthesis, and identification of highly potent benzhydrol derivatives as squalene synthase inhibitors (compound 1). Unfortunately, the in vivo efficacies of the compounds were not enough for acquiring the clinical candidate. We continued our investigation to obtain a more in vivo efficacious template than the benzhydrol template. In our effort, we focused on a benzoxazepine ring and designed a new tricyclic scaffold by the incorporation of heterocycle into it. Prepared pyrrolobenzoxazepine derivatives showed further efficient in vitro and in vivo activities.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Farnesil-Difosfato Farnesiltransferase/antagonistas & inibidores , Administração Oral , Animais , Anticolesterolemiantes/síntese química , Anticolesterolemiantes/química , Anticolesterolemiantes/farmacologia , Compostos Benzidrílicos/síntese química , Compostos Benzidrílicos/química , Compostos Benzidrílicos/farmacologia , Sítios de Ligação , Callithrix , Domínio Catalítico , Células Cultivadas , Simulação por Computador , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Farnesil-Difosfato Farnesiltransferase/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Ratos , Relação Estrutura-AtividadeRESUMO
A series of 4-oxo-4H-pyrido[1,2-a]pyrimidine derivatives, substituted at the 2-position with piperidines bearing quaternary ammonium salt side chains, were synthesized and evaluated for their ability to potentiate the activity of the fluoroquinolone levofloxacin (LVFX) and the beta-lactam aztreonam (AZT) in Pseudomonas aeruginosa. Attachment of the charged entity using an N-ethylcarbamoyloxy linker led to the discovery of the highly soluble compound 22 (D13-9001), which maintained good potency in vitro and displayed excellent activity in vivo in a rat pneumonia model of P. aeruginosa.