title: Preclinical and Early Clinical Profile of a Highly Selective and Potent Oral Inhibitor of Aldosterone Synthase (CYP11B2).
abstract: Primary hyperaldosteronism is a common cause of resistant hypertension. Aldosterone is produced in the adrenal by aldosterone synthase (AS, encoded by the gene CYP11B2). AS shares 93% homology to 11β-hydroxylase (encoded by the gene CYP11B1), responsible for cortisol production. This homology has hitherto impeded the development of a drug, which selectively suppresses aldosterone but not cortisol production, as a new treatment for primary hyperaldosteronism. We now report the development of RO6836191 as a potent (Ki 13 nmol/L) competitive inhibitor of AS, with in vitro selectivity >100-fold over 11β-hydroxylase. In cynomolgus monkeys challenged with synthetic adrenocorticotropic hormone, single doses of RO6836191 inhibited aldosterone synthesis without affecting the adrenocorticotropic hormone-induced rise in cortisol. In repeat-dose toxicity studies in monkeys, RO6836191 reproduced the adrenal changes of the AS-/-mouse: expansion of the zona glomerulosa; increased expression of AS (or disrupted green fluorescent protein gene in the AS-/-mouse); hypertrophy, proliferation, and apoptosis of zona glomerulosa cells. These changes in the monkey were partially reversible and partially preventable by electrolyte supplementation and treatment with an angiotensin-converting enzyme inhibitor. In healthy subjects, single doses of RO6836191, across a 360-fold dose range, reduced plasma and urine aldosterone levels with maximum suppression at a dose of 10 mg, but unchanged cortisol, on adrenocorticotropic hormone challenge, up to 360 mg, and increase in the precursors 11-deoxycorticosterone and 11-deoxycortisol only at or >90 mg. In conclusion, RO6836191 demonstrates that it is possible to suppress aldosterone production completely in humans without affecting cortisol production.
  
  
  
  URL: http://www.clinicaltrials.gov. Unique identifier: NCT01995383.
authors.affiliation: From the Clinical Pharmacology (K.B., D.S., M.-L.D.), Biostatistics (G.P.), Discovery (K.A.), Pharmaceutical Sciences (S.M., M.C.D.V.M.), and Translational Medicine, Cardiovascular Diseases (P.F.), Pharma Research and Early Development, Roche Innovation Center Basel, Switzerland; and Clinical Pharmacology, William Harvey Research Institute, Queen Mary University of London, United Kingdom (M.J.B). katrijn.bogman@roche.com.
authors.forename: Katrijn
authors.initials: K
authors.lastname: Bogman
authors.affiliation: From the Clinical Pharmacology (K.B., D.S., M.-L.D.), Biostatistics (G.P.), Discovery (K.A.), Pharmaceutical Sciences (S.M., M.C.D.V.M.), and Translational Medicine, Cardiovascular Diseases (P.F.), Pharma Research and Early Development, Roche Innovation Center Basel, Switzerland; and Clinical Pharmacology, William Harvey Research Institute, Queen Mary University of London, United Kingdom (M.J.B).
authors.forename: Dietmar
authors.initials: D
authors.lastname: Schwab
authors.affiliation: From the Clinical Pharmacology (K.B., D.S., M.-L.D.), Biostatistics (G.P.), Discovery (K.A.), Pharmaceutical Sciences (S.M., M.C.D.V.M.), and Translational Medicine, Cardiovascular Diseases (P.F.), Pharma Research and Early Development, Roche Innovation Center Basel, Switzerland; and Clinical Pharmacology, William Harvey Research Institute, Queen Mary University of London, United Kingdom (M.J.B).
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Delporte
authors.affiliation: From the Clinical Pharmacology (K.B., D.S., M.-L.D.), Biostatistics (G.P.), Discovery (K.A.), Pharmaceutical Sciences (S.M., M.C.D.V.M.), and Translational Medicine, Cardiovascular Diseases (P.F.), Pharma Research and Early Development, Roche Innovation Center Basel, Switzerland; and Clinical Pharmacology, William Harvey Research Institute, Queen Mary University of London, United Kingdom (M.J.B).
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Palermo
authors.affiliation: From the Clinical Pharmacology (K.B., D.S., M.-L.D.), Biostatistics (G.P.), Discovery (K.A.), Pharmaceutical Sciences (S.M., M.C.D.V.M.), and Translational Medicine, Cardiovascular Diseases (P.F.), Pharma Research and Early Development, Roche Innovation Center Basel, Switzerland; and Clinical Pharmacology, William Harvey Research Institute, Queen Mary University of London, United Kingdom (M.J.B).
authors.forename: Kurt
authors.initials: K
authors.lastname: Amrein
authors.affiliation: From the Clinical Pharmacology (K.B., D.S., M.-L.D.), Biostatistics (G.P.), Discovery (K.A.), Pharmaceutical Sciences (S.M., M.C.D.V.M.), and Translational Medicine, Cardiovascular Diseases (P.F.), Pharma Research and Early Development, Roche Innovation Center Basel, Switzerland; and Clinical Pharmacology, William Harvey Research Institute, Queen Mary University of London, United Kingdom (M.J.B).
authors.forename: Susanne
authors.initials: S
authors.lastname: Mohr
authors.affiliation: From the Clinical Pharmacology (K.B., D.S., M.-L.D.), Biostatistics (G.P.), Discovery (K.A.), Pharmaceutical Sciences (S.M., M.C.D.V.M.), and Translational Medicine, Cardiovascular Diseases (P.F.), Pharma Research and Early Development, Roche Innovation Center Basel, Switzerland; and Clinical Pharmacology, William Harvey Research Institute, Queen Mary University of London, United Kingdom (M.J.B).
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: De Vera Mudry
authors.affiliation: From the Clinical Pharmacology (K.B., D.S., M.-L.D.), Biostatistics (G.P.), Discovery (K.A.), Pharmaceutical Sciences (S.M., M.C.D.V.M.), and Translational Medicine, Cardiovascular Diseases (P.F.), Pharma Research and Early Development, Roche Innovation Center Basel, Switzerland; and Clinical Pharmacology, William Harvey Research Institute, Queen Mary University of London, United Kingdom (M.J.B).
authors.forename: Morris J
authors.initials: MJ
authors.lastname: Brown
authors.affiliation: From the Clinical Pharmacology (K.B., D.S., M.-L.D.), Biostatistics (G.P.), Discovery (K.A.), Pharmaceutical Sciences (S.M., M.C.D.V.M.), and Translational Medicine, Cardiovascular Diseases (P.F.), Pharma Research and Early Development, Roche Innovation Center Basel, Switzerland; and Clinical Pharmacology, William Harvey Research Institute, Queen Mary University of London, United Kingdom (M.J.B).
authors.forename: Philippe
authors.initials: P
authors.lastname: Ferber
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D019405:Cytochrome P-450 CYP11B2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D006801:Humans; D006929:Hyperaldosteronism / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D006973:Hypertension / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D008252:Macaca fascicularis
chemical_list: D004791:Enzyme Inhibitors; D019405:Cytochrome P-450 CYP11B2
keywords: CYP11B2; adrenal cortex; aldosterone; cytochrome P-450; hydrocortisone; hyperaldosteronism; zona glomerulosa