title: Discovery of 4-Aryl-5,6,7,8-tetrahydroisoquinolines as Potent, Selective, and Orally Active Aldosterone Synthase (CYP11B2) Inhibitors: In Vivo Evaluation in Rodents and Cynomolgus Monkeys.
abstract: Inappropriately high levels of aldosterone are associated with many serious medical conditions, including renal and cardiac failure. A focused screen hit has been optimized into a potent and selective aldosterone synthase (CYP11B2) inhibitor with in vitro activity against rat, mouse, human, and cynomolgus monkey enzymes, showing a selectivity factor of 160 against cytochrome CYP11B1 in the last species. The novel tetrahydroisoquinoline compound (+)-(R)-6 selectively reduced aldosterone plasma levels in vivo in a dose-dependent manner in db/db mice and cynomolgus monkeys. The selectivity against CYP11B1 as predicted by cellular inhibition data and free plasma fraction translated well to Synacthen challenged cynomolgus monkeys up to a dose of 0.1 mg kg(-1). This compound, displaying good in vivo potency and selectivity in mice and monkeys, is ideally suited to perform mechanistic studies in relevant rodent models and to provide the information necessary for translation to non-human primates and ultimately to man.
authors.affiliation: Medicinal Chemistry, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: Rainer E
authors.initials: RE
authors.lastname: Martin
authors.affiliation: Medicinal Chemistry, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: Johannes D
authors.initials: JD
authors.lastname: Aebi
authors.affiliation: Medicinal Chemistry, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: Benoit
authors.initials: B
authors.lastname: Hornsperger
authors.affiliation: Medicinal Chemistry, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: Hans-Jakob
authors.initials: HJ
authors.lastname: Krebs
authors.affiliation: Medicinal Chemistry, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: Bernd
authors.initials: B
authors.lastname: Kuhn
authors.affiliation: Medicinal Chemistry, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kuglstatter
authors.affiliation: Medicinal Chemistry, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: André M
authors.initials: AM
authors.lastname: Alker
authors.affiliation: Medicinal Chemistry, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: Hans Peter
authors.initials: HP
authors.lastname: Märki
authors.affiliation: Discovery Technologies, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Müller
authors.affiliation: Discovery Technologies, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: Dominique
authors.initials: D
authors.lastname: Burger
authors.affiliation: Pharmaceutical Sciences, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Shanghai, F. Hoffmann-La Roche Ltd. , 720 Cai Lun Road, Building 5, Pudong, Shanghai 201203, China.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Ottaviani
authors.affiliation: Neuroscience, Ophthalmology and Rare Diseases, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: William
authors.initials: W
authors.lastname: Riboulet
authors.affiliation: Discovery Cardiovascular and Metabolic Disease, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: Philippe
authors.initials: P
authors.lastname: Verry
authors.affiliation: Medicinal Chemistry, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Shanghai, F. Hoffmann-La Roche Ltd. , 720 Cai Lun Road, Building 5, Pudong, Shanghai 201203, China.
authors.forename: Xuefei
authors.initials: X
authors.lastname: Tan
authors.affiliation: Discovery Infectious Disease, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: Kurt
authors.initials: K
authors.lastname: Amrein
authors.affiliation: Medicinal Chemistry, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Mayweg
mesh_terms: D000450:Aldosterone / Q000097:blood; D000818:Animals; D019405:Cytochrome P-450 CYP11B2 / Q000037:antagonists & inhibitors*; D015195:Drug Design; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D000451:Mineralocorticoid Receptor Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D008958:Models, Molecular; D051381:Rats; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D000451:Mineralocorticoid Receptor Antagonists; D044005:Tetrahydroisoquinolines; D000450:Aldosterone; D019405:Cytochrome P-450 CYP11B2