RESUMEN
We report the discovery and hit-to-lead optimization of a structurally novel indazole series of CYP11B2 inhibitors. Benchmark compound 34 from this series displays potent inhibition of CYP11B2, high selectivity versus related steroidal and hepatic CYP targets, and lead-like physical and pharmacokinetic properties. On the basis of these and other data, the indazole series was progressed to lead optimization for further refinement.
Asunto(s)
Antihipertensivos/farmacología , Citocromo P-450 CYP11B2/antagonistas & inhibidores , Hipertensión/tratamiento farmacológico , Indazoles/farmacología , Animales , Antihipertensivos/síntesis química , Antihipertensivos/farmacocinética , Inhibidores de la Aromatasa/síntesis química , Inhibidores de la Aromatasa/farmacocinética , Inhibidores de la Aromatasa/farmacología , Línea Celular , Cricetulus , Inhibidores del Citocromo P-450 CYP2D6/síntesis química , Inhibidores del Citocromo P-450 CYP2D6/farmacocinética , Inhibidores del Citocromo P-450 CYP2D6/farmacología , Humanos , Indazoles/síntesis química , Indazoles/farmacocinética , Macaca mulatta , Masculino , Ratas Sprague-Dawley , Estereoisomerismo , Esteroide 11-beta-Hidroxilasa/antagonistas & inhibidoresRESUMEN
We report the discovery of a benzimidazole series of CYP11B2 inhibitors. Hit-to-lead and lead optimization studies identified compounds such as 32, which displays potent CYP11B2 inhibition, high selectivity versus related CYP targets, and good pharmacokinetic properties in rat and rhesus. In a rhesus pharmacodynamic model, 32 produces dose-dependent aldosterone lowering efficacy, with no apparent effect on cortisol levels.
RESUMEN
Hit-to-lead efforts resulted in the discovery of compound 19, a potent CYP11B2 inhibitor that displays high selectivity vs related CYPs, good pharmacokinetic properties in rat and rhesus, and lead-like physical properties. In a rhesus pharmacodynamic model, compound 19 displays robust, dose-dependent aldosterone lowering efficacy, with no apparent effect on cortisol levels.