RESUMO
Chemical evolution of a HTS-based fragment hit resulted in the identification of N-(1-adamantyl)-2-[4-(2-tetrahydropyran-4-ylethyl)piperazin-1-yl]acetamide, a novel, selective T-type calcium channel (Ca(v)3.2) inhibitor with in vivo antihypertensive effect in rats.
Assuntos
Acetamidas/farmacologia , Anti-Hipertensivos/farmacologia , Canais de Cálcio Tipo T/metabolismo , Descoberta de Drogas , Acetamidas/síntese química , Acetamidas/química , Animais , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/química , Relação Dose-Resposta a Droga , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/metabolismo , Ensaios de Triagem em Larga Escala , Humanos , Estrutura Molecular , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Inhibition of acetyl-CoA carboxylases has the potential for modulating long chain fatty acid biosynthesis and mitochondrial fatty acid oxidation. Hybridization of weak inhibitors of ACC2 provided a novel, moderately potent but lipophilic series. Optimization led to compounds 33 and 37, which exhibit potent inhibition of human ACC2, 10-fold selectivity over inhibition of human ACC1, good physical and in vitro ADME properties and good bioavailability. X-ray crystallography has shown this series binding in the CT-domain of ACC2 and revealed two key hydrogen bonding interactions. Both 33 and 37 lower levels of hepatic malonyl-CoA in vivo in obese Zucker rats.
