RESUMO
The development of renin inhibitors with favorable oral pharmacokinetic profiles has been a longstanding challenge for the pharmaceutical industry. As part of our work to identify inhibitors of BACE1, we have previously developed iminopyrimidinones as a novel pharmacophore for aspartyl protease inhibition. In this letter we describe how we modified substitution around this pharmacophore to develop a potent, selective and orally active renin inhibitor.
Assuntos
Inibidores Enzimáticos/farmacologia , Iminas/farmacologia , Pirimidinonas/farmacologia , Renina/antagonistas & inibidores , Administração Oral , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Iminas/síntese química , Iminas/química , Modelos Moleculares , Estrutura Molecular , Pirimidinonas/síntese química , Pirimidinonas/química , Renina/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of pyrrolo-benzo-1,4-diazine analogs have been synthesized and displayed potent Nav1.7 inhibitory activity and moderate selectivity over Nav1.5. The syntheses, structure-activity relationships, and selected pharmacokinetic data of these analogs are described. Compound 41 displayed anti-nociceptive efficacy in the rat CFA pain model at 100 mpk oral dosing.
Assuntos
Descoberta de Drogas , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Quinoxalinas/farmacologia , Bloqueadores dos Canais de Sódio/farmacologia , Compostos de Espiro/farmacologia , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Quinoxalinas/síntese química , Quinoxalinas/química , Bloqueadores dos Canais de Sódio/síntese química , Bloqueadores dos Canais de Sódio/química , Compostos de Espiro/síntese química , Compostos de Espiro/química , Relação Estrutura-AtividadeRESUMO
A novel tetrakis(terpyridinyl)porphyrin derivative and its Ru(II) complexes were efficiently synthesized using microwave enhanced synthesis and shown to possess photovoltaic properties. Transmission electron microscopy and selected area electron diffraction were used to investigate its nanowire self-assembly.
