ABSTRACT
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.
Subject(s)
Antihypertensive Agents/pharmacology , Cytochrome P-450 CYP11B2/antagonists & inhibitors , Hypertension/drug therapy , Indazoles/pharmacology , Animals , Antihypertensive Agents/chemical synthesis , Antihypertensive Agents/pharmacokinetics , Aromatase Inhibitors/chemical synthesis , Aromatase Inhibitors/pharmacokinetics , Aromatase Inhibitors/pharmacology , Cell Line , Cricetulus , Cytochrome P-450 CYP2D6 Inhibitors/chemical synthesis , Cytochrome P-450 CYP2D6 Inhibitors/pharmacokinetics , Cytochrome P-450 CYP2D6 Inhibitors/pharmacology , Humans , Indazoles/chemical synthesis , Indazoles/pharmacokinetics , Macaca mulatta , Male , Rats, Sprague-Dawley , Stereoisomerism , Steroid 11-beta-Hydroxylase/antagonists & inhibitorsABSTRACT
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.
ABSTRACT
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.
