Title:Progress Towards Clinically Useful Aldosterone Synthase Inhibitors
Volume: 13
Issue: 12
Author(s): Matthew A. Cerny
Affiliation:
Keywords:
Aldosterone, aldosterone synthase, cortisol, cortisol synthase, cytochrome P450, inhibitors.
Abstract: Owing to the high degree of similarity between aldosterone synthase (CYP11B2) and cortisol synthase
(CYP11B1), the design of selective inhibitors of one or the other of these two enzymes was, at one time, thought to be
impossible. Through development of novel enzyme screening assays and significant medicinal chemistry efforts, highly
potent inhibitors of CYP11B2 have been identified with selectivities approaching 1000-fold between the two enzymes.
Many of these molecules also possess selectivity against other steroidogenic cytochromes P450 (e.g. CYP17A1 and
CYP19A1) as well as hepatic drug metabolizing P450s. Though not as well developed or explored, inhibitors of
CYP11B1, with selectivities approaching 50-fold, have also been identified. The therapeutic benefits of affecting the
renin-angiotensin-aldosterone system have been well established with the therapeutically useful angiotensin-converting
enzymes inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists. Data regarding the additional
benefits of an aldosterone synthase inhibitor (ASi) are beginning to emerge from animal models and human clinical
trials. Despite great promise and much progress, additional challenges still exist in the path towards development of a
therapeutically useful ASi.
