Preclinical and Early Clinical Profile of a Highly Selective and Potent Oral Inhibitor of Aldosterone Synthase (CYP11B2)

• DOI: 10.1161/hypertensionaha.116.07716
• Publication Date: 2016-11-22T03:50:23Z
• Authors: Katrijn Bogman; Dietmar Schwab; Marie-Laure Delporte; Giuseppe Palermo; Kurt Amrein; Susanne Mohr; Maria Cristina De...; Morris J. Brown; Philippe Ferber
• Keywords: Aldosterone synthase

Primary hyperaldosteronism is a common cause of resistant hypertension. Aldosterone produced in the adrenal by aldosterone synthase (AS, encoded gene CYP11B2). AS shares 93% homology to 11β-hydroxylase (encoded CYP11B1), responsible for cortisol production. This has hitherto impeded development drug, which selectively suppresses but not production, as new treatment primary hyperaldosteronism. We now report RO6836191 potent (Ki 13 nmol/L) competitive inhibitor AS, with vitro selectivity >100-fold over 11β-hydroxylase. In cynomolgus monkeys challenged synthetic adrenocorticotropic hormone, single doses inhibited synthesis without affecting hormone-induced rise cortisol. repeat-dose toxicity studies monkeys, reproduced changes AS-/- mouse: expansion zona glomerulosa; increased expression (or disrupted green fluorescent protein mouse); hypertrophy, proliferation, and apoptosis glomerulosa cells. These monkey were partially reversible preventable electrolyte supplementation an angiotensin-converting enzyme inhibitor. healthy subjects, RO6836191, across 360-fold dose range, reduced plasma urine levels maximum suppression at 10 mg, unchanged cortisol, on hormone challenge, up 360 increase precursors 11-deoxycorticosterone 11-deoxycortisol only or >90 mg. conclusion, demonstrates that it possible suppress production completely humans production.URL: http://www.clinicaltrials.gov. Unique identifier: NCT01995383.