RESUMEN
The discovery and SAR of a series of potent renin inhibitors possessing a novel 3,4-diarylpiperidine scaffold are described herein. The resulting compound 38 exhibit low nanomolar plasma renin IC(50), had a clean CYP 3A4 profile and displayed micromolar affinity for the hERG channel. Furthermore, it was found to be efficacious in the double transgenic rat hypertension model and show good to moderate oral bioavailability in two animal species.
Asunto(s)
Antihipertensivos/química , Antihipertensivos/uso terapéutico , Hipertensión/tratamiento farmacológico , Piperidinas/química , Piperidinas/uso terapéutico , Renina/antagonistas & inhibidores , Animales , Antihipertensivos/farmacocinética , Antihipertensivos/farmacología , Disponibilidad Biológica , Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A , Perros , Canales de Potasio Éter-A-Go-Go/metabolismo , Humanos , Piperidinas/farmacocinética , Piperidinas/farmacología , Ratas , Ratas Sprague-Dawley , Ratas Transgénicas , Renina/metabolismo , Relación Estructura-ActividadRESUMEN
Time-dependent inhibitors of CYPs have the potential to perpetrate drug-drug interactions in the clinical setting. After finding that several leading compounds in a novel series of substituted amino propanamide renin inhibitors inactivated CYP3A4 in an NADPH-dependent and time-dependent manner, a search to identify the cause of this liability was initiated. Extensive SAR revealed that the amide bridge present in compound 1 as a possible culprit. Through the installation of a metabolic soft spot distal to this moiety, potent renin inhibitors with improved CYP profile were identified.
Asunto(s)
Inhibidores del Citocromo P-450 CYP3A , Inhibidores Enzimáticos/farmacología , Propionatos/química , Renina/antagonistas & inhibidores , Amidas/química , Citocromo P-450 CYP3A , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Humanos , Concentración 50 Inhibidora , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimologíaRESUMEN
The discovery and SAR of a series of potent renin inhibitors possessing a novel biaryl scaffold are described herein. Molecular modeling revealed that the cyclopropylamide spacer present in 1 can be replaced by a simple, substituted aromatic ring such as a toluene in 2. The resulting compounds exhibit subnanomolar renin IC(50) and good oral bioavailability in rats.
Asunto(s)
Bibencilos/química , Inhibidores Enzimáticos/química , Renina/antagonistas & inhibidores , Administración Oral , Amidas/química , Animales , Bibencilos/síntesis química , Bibencilos/farmacocinética , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Ratas , Renina/metabolismo , Relación Estructura-ActividadRESUMEN
The discovery and SAR of a new series of substituted amino propanamide renin inhibitors are herein described. This work has led to the preparation of compounds with in vitro and in vivo profiles suitable for further development. Specifically, challenges pertaining to oral bioavailability, covalent binding and time-dependent CYP 3A4 inhibition were overcome thereby culminating in the identification of compound 50 as an optimized renin inhibitor with good efficacy in the hypertensive double-transgenic rat model.
