RESUMO
Lung selective inhibition of the endothelial sodium channel (ENaC) is a potential mutation agnostic treatment of Cystic Fibrosis (CF). We describe the discovery and development of BI 1265162, the first ENaC inhibitor devoid of the amiloride structural motif that entered clinical trials. The design of BI 1265162 focused on its suitability for inhalation via the Respimat® Soft Mist™ Inhaler and a long duration of action. A convergent and scalable route for the synthesis of BI 1265162 as dihydrogen phosphate salt is presented, that was applied to support clinical trials. A phase 2 study with BI 1265162 did not provide a clear sign of clinical benefit. Whether ENaC inhibition will be able to hold its promise for CF patients remains an open question.
Assuntos
Fibrose Cística , Humanos , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Bloqueadores dos Canais de Sódio/uso terapêutico , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Canais Epiteliais de Sódio/genética , Canais Epiteliais de Sódio/uso terapêutico , Amilorida/farmacologia , Amilorida/uso terapêutico , Sódio/metabolismo , Sódio/uso terapêuticoRESUMO
[reaction: see text] A concise route to an advance precursor (3) of the central core of amphidinol 3, a natural occurring polyketide, has been developed by applying a reductive lithiation as key step. The origin of the diastereoselectivity of this reaction was comprehensively studied for nucleophilic C-glycoside donor 5 and differently protected analogues.