RESUMO
SAR studies of the substitution effect on the central phenyl ring of the biphenyl scaffold were carried out using anacetrapib (9a) as the benchmark. The results revealed that the new analogs with substitutions to replace trifluoromethyl (9a) had a significant impact on CETP inhibition in vitro. In fact, analogs with some small groups were as potent or more potent than the CF(3) derivative for CETP inhibition. Five of these new analogs raised HDL-C significantly (>20mg/dL). None of them however was better than anacetrapib in vivo. The synthesis and biological evaluation of these CETP inhibitors are described.
Assuntos
Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Oxazolidinonas/farmacologia , Animais , Química Farmacêutica/métodos , HDL-Colesterol/metabolismo , Relação Dose-Resposta a Droga , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Camundongos , Camundongos Transgênicos , Modelos Químicos , Relação Estrutura-AtividadeRESUMO
A new class of CETP inhibitors was designed and prepared. These compounds are potent both in vitro and in vivo. The most active compound (12d) has shown an ability to raise HDL significantly in transgenic mouse PD model.
Assuntos
Benzilaminas/química , Compostos de Bifenilo/química , Carbamatos/química , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Animais , Benzilaminas/síntese química , Benzilaminas/farmacologia , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/farmacologia , Carbamatos/síntese química , Carbamatos/farmacologia , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Modelos Animais de Doenças , Desenho de Fármacos , Lipoproteínas HDL/metabolismo , Camundongos , Camundongos Transgênicos , Relação Estrutura-AtividadeRESUMO
The development of the structure-activity studies leading to the discovery of anacetrapib is described. These studies focused on varying the substitution of the oxazolidinone ring of the 5-aryloxazolidinone system. Specifically, it was found that substitution of the 4-position with a methyl group with the cis-stereochemistry relative to the 5-aryl group afforded compounds with increased cholesteryl ester transfer protein (CETP) inhibition potency and a robust in vivo effect on increasing HDL-C levels in transgenic mice expressing cynomolgus monkey CETP.