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
We have recently reported the discovery of the new benzhydrol template, which has a highly potent inhibitory activity for squalene synthase, as typified by compound 1 (SSI IC(50)=0.85 nM). However, it was composed of a pair of easy rotatable atropisomers. In the effort to fix the isomerization, a highly potent alkoxy-aminobenzhydrol scaffold was developed. Some of these acquired compounds demonstrating strong cholesterol synthesis inhibitory activities in a rat hepatic cell. Moreover, two of the series compounds exhibited specific plasma lipid-lowering effects in in vivo animal models.
Assuntos
Anticolesterolemiantes/química , Compostos Benzidrílicos/química , Inibidores Enzimáticos/química , Farnesil-Difosfato Farnesiltransferase/antagonistas & inibidores , Administração Oral , Animais , Anticolesterolemiantes/síntese química , Anticolesterolemiantes/farmacocinética , Compostos Benzidrílicos/síntese química , Compostos Benzidrílicos/farmacocinética , Sítios de Ligação , Callithrix , Simulação por Computador , Cricetinae , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Farnesil-Difosfato Farnesiltransferase/metabolismo , Feminino , Hepatócitos/efeitos dos fármacos , Isomerismo , Masculino , Modelos Animais , Ratos , Relação Estrutura-AtividadeRESUMO
To obtain small and efficient squalene synthase inhibitors, a flexible 2-aminobenzhydrol open form structure was designed and showed potent inhibitory activity comparable to 4,1-benzoxazepin compounds. Further chemical modification led to the discovery of a novel template with a strong squalene synthase inhibitory activity, and its basic structure-activity relationship was revealed. The X-ray crystallographic data of compound 12 bound to the active site of squalene synthase provided an important insight into the binding mode of this alternative template that formed 11-membered ring conformations with an intramolecular hydrogen bond.