RESUMEN
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.
Asunto(s)
Fibrosis Quística , Humanos , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/genética , Bloqueadores de los Canales de Sodio/uso terapéutico , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Canales Epiteliales de Sodio/genética , Canales Epiteliales de Sodio/uso terapéutico , Amilorida/farmacología , Amilorida/uso terapéutico , Sodio/metabolismo , Sodio/uso terapéuticoRESUMEN
We report a SAR of non-steroidal glucocorticoid mimetics that utilize indoles as A-ring mimetics. Detailed SAR is discussed with a focus on improving PR and MR selectivity, GR agonism, and in vitro dissociation profile. SAR analysis led to compound (R)-33 which showed high PR and MR selectivity, potent agonist activity, and reduced transactivation activity in the MMTV and aromatase assays. The compound is equipotent to prednisolone in the LPS-TNF model of inflammation. In mouse CIA, at 30 mg/kg compound (R)-33 inhibited disease progression with an efficacy similar to the 3 mg/kg dose of prednisolone.
Asunto(s)
Glucocorticoides/química , Glucocorticoides/farmacología , Indoles/química , Indoles/farmacología , Receptores de Glucocorticoides/agonistas , Receptores de Glucocorticoides/metabolismo , Animales , Células HeLa , Humanos , Ratones , Modelos Moleculares , Relación Estructura-ActividadRESUMEN
SAR studies to improve the selectivity and metabolic stability of a class of recently discovered MMP-13 inhibitors are reported. Improved selectivity was achieved by modifying interactions with the S1' pocket. Metabolic stability was improved through reduction of inhibitor lipophilicity. This translated into lower in vivo clearance for the preferred compound.
