Discovery of 3‑Pyridyl Isoindolin-1-one Derivatives as Potent, Selective, and Orally Active Aldosterone Synthase (CYP11B2) Inhibitors

Aldosterone synthase (CYP11B2) inhibitors
have been explored in
recent years as an alternative therapeutic option to mineralocorticoid
receptor (MR) antagonists to reduce elevated aldosterone levels, which
are associated with deleterious effects on various organ systems including
the heart, vasculature, kidney, and central nervous system (CNS).
A benzamide pyridine hit derived from a focused screen was successfully
developed into a series of potent and selective 3-pyridyl isoindolin-1-ones
CYP11B2 inhibitors. Our systematic structure–activity relationship
study enabled us to identify unique structural features that result
in high selectivity against the closely homologous cortisol synthase
(CYP11B1). We evaluated advanced lead molecules, exemplified by compound 52, in an in vivo cynomolgus monkey acute
adrenocorticotropic hormone (ACTH) challenge model and demonstrated
a superior 100-fold in vivo selectivity against CYP11B1.