Inhibitors of Aldosterone Synthase

The mineralocorticoid aldosterone is an important regulator of blood pressure and electrolyte balance. However, excess aldosterone can be deleterious as a driver of inflammation, vascular remodeling and tissue fibrosis associated with cardiometabolic diseases. Mineralocorticoid receptor antagonists (MRA) and renin-angiotensin-aldosterone system (RAAS) antagonists are current clinical therapies used to antagonize deleterious effects of aldosterone in patients. MRAs compete with aldosterone for binding at its cognate receptor thereby limiting its effect while RAS antagonists reduce aldosterone levels indirectly by blocking the stimulatory effect of angiotensin. Both MRAs and RAS antagonists can result in incomplete inhibition of the harmful effects of excess aldosterone. Aldosterone synthase (AS) inhibitors (ASI) attenuate the production of aldosterone directly and have been proposed as an alternative to MRAs and RAS blockers. Cortisol synthase (CS) is an enzyme closely related to AS and responsible for generating the important glucocorticoid cortisol, required for maintaining critical metabolic and immune responses. The importance of selectivity against CS is shown by early examples of ASIs that were only modestly selective and as such, attenuated cortisol responses when evaluated in patients. Recently, next-generation, highly selective ASIs have been described and are presently being evaluated in the clinic as an alternative to angiotensin and MR antagonists for cardiometabolic disease. Herein we provide a brief review of the challenges associated with discovery of selective ASIs and the transition from the early compounds that paved the way toward the next-generation of highly selective ASIs currently under development.