RESUMO
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.
Assuntos
Anti-Hipertensivos/farmacologia , Citocromo P-450 CYP11B2/antagonistas & inibidores , Hipertensão/tratamento farmacológico , Indazóis/farmacologia , Animais , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/farmacocinética , Inibidores da Aromatase/síntese química , Inibidores da Aromatase/farmacocinética , Inibidores da Aromatase/farmacologia , Linhagem Celular , Cricetulus , Inibidores do Citocromo P-450 CYP2D6/síntese química , Inibidores do Citocromo P-450 CYP2D6/farmacocinética , Inibidores do Citocromo P-450 CYP2D6/farmacologia , Humanos , Indazóis/síntese química , Indazóis/farmacocinética , Macaca mulatta , Masculino , Ratos Sprague-Dawley , Estereoisomerismo , Esteroide 11-beta-Hidroxilase/antagonistas & inibidoresRESUMO
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.
RESUMO
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.