ABSTRACT
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.
ABSTRACT
Efforts were dedicated to develop potent and brain penetrant prolylcarboxypeptidase (PrCP) inhibitors by replacing the amide group of original leads 1 and 2 with heterocycles. Aminopyrimidines including compound 32a were identified to display good PrCP inhibitory activity (32a, IC(50)=43 nM) and impressive ability to penetrate brain in mice (brain/plasma ratio: 1.4).
Subject(s)
Amines/chemical synthesis , Brain/drug effects , Carboxypeptidases/antagonists & inhibitors , Drug Discovery , Enzyme Inhibitors , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/pharmacology , Amides/chemistry , Amines/chemistry , Amines/pharmacology , Animals , Brain/enzymology , Enzyme Activation/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Heterocyclic Compounds/chemistry , Inhibitory Concentration 50 , Mice , Molecular Structure , Structure-Activity RelationshipABSTRACT
A series of benzodihydroisofurans were discovered as novel, potent, bioavailable and brain-penetrant prolylcarboxypeptidase (PrCP) inhibitors. The structure-activity relationship (SAR) is focused on improving PrCP activity and metabolic stability, and reducing plasma protein binding. In the established diet-induced obese (eDIO) mouse model, compound ent-3a displayed target engagement both in plasma and in brain. However, this compound failed to induce significant body weight loss in eDIO mice in a five-day study.
Subject(s)
Carboxypeptidases/antagonists & inhibitors , Drug Discovery , Enzyme Inhibitors/pharmacology , Furans/chemistry , Furans/pharmacology , Animals , Cells, Cultured , Disease Models, Animal , Drug Stability , Enzyme Activation/drug effects , Furans/chemical synthesis , Humans , Mice , Mice, Obese , Molecular Structure , Structure-Activity RelationshipABSTRACT
Efforts to modify the central proline portion of lead compound 4 lead to the discovery of novel prolylcarboxypeptidase (PrCP) inhibitors. Especially, replacement with alanine afforded compound 19 displaying more potent human and mouse PrCP inhibitory activity than 4 and an overall comparable profile.
