RESUMO
Aldosterone is a hormone that exerts manifold deleterious effects on the kidneys, blood vessels, and heart which can lead to pathophysiological consequences. Inhibition of the mineralocorticoid receptor (MR) is a proven therapeutic concept for the management of associated diseases. Use of the currently marketed MR antagonists spironolactone and eplerenone is restricted, however, due to a lack of selectivity in spironolactone and the lower potency and efficacy of eplerenone. Several pharmaceutical companies have implemented programs to identify drugs that overcome the known liabilities of steroidal MR antagonists. Herein we disclose an extended SAR exploration starting from cyano-1,4-dihydropyridines that were identified by high-throughput screening. Our efforts led to the identification of a dihydronaphthyridine, BAY 94-8862, which is a potent, selective, and orally available nonsteroidal MR antagonist currently under investigation in a clinical phaseâ II trial.
Assuntos
Insuficiência Cardíaca/tratamento farmacológico , Nefropatias/tratamento farmacológico , Antagonistas de Receptores de Mineralocorticoides/química , Naftiridinas/química , Receptores de Mineralocorticoides/química , Animais , Sítios de Ligação , Doença Crônica , Simulação por Computador , Avaliação Pré-Clínica de Medicamentos , Insuficiência Cardíaca/complicações , Humanos , Nefropatias/complicações , Antagonistas de Receptores de Mineralocorticoides/síntese química , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Naftiridinas/síntese química , Naftiridinas/uso terapêutico , Potássio/urina , Estrutura Terciária de Proteína , Ratos , Receptores de Mineralocorticoides/metabolismo , Sódio/urinaRESUMO
Highly enantioenriched mixed benzoins are obtained selectively through a biocatalytical cross-coupling reaction of aromatic aldehydes using ThDP-dependent enzymes.
