1. Discovery of 4-Aryl-5,6,7,8-tetrahydroisoquinolinesas Potent, Selective, and Orally Active Aldosterone Synthase (CYP11B2)Inhibitors: In Vivo Evaluation in Rodents and Cynomolgus Monkeys.
- Author
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RainerE. Martin, Johannes D. Aebi, Benoit Hornsperger, Hans-Jakob Krebs, Bernd Kuhn, Andreas Kuglstatter, AndréM. Alker, Hans Peter Märki, Stephan Müller, Dominique Burger, Giorgio Ottaviani, William Riboulet, Philippe Verry, Xuefei Tan, Kurt Amrein, and Alexander V. Mayweg
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TETRAHYDROISOQUINOLINES , *DRUG development , *ALDOSTERONE synthesis , *HEART failure treatment , *LABORATORY rodents - Abstract
Inappropriately high levels of aldosteroneare associated withmany serious medical conditions, including renal and cardiac failure.A focused screen hit has been optimized into a potent and selectivealdosterone synthase (CYP11B2) inhibitor with in vitro activity againstrat, mouse, human, and cynomolgus monkey enzymes, showing a selectivityfactor of 160 against cytochrome CYP11B1 in the last species. Thenovel tetrahydroisoquinoline compound (+)-(R)-6selectively reduced aldosterone plasma levels in vivo ina dose-dependent manner in db/db mice and cynomolgus monkeys. Theselectivity against CYP11B1 as predicted by cellular inhibition dataand free plasma fraction translated well to Synacthen challenged cynomolgusmonkeys 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 rodentmodels and to provide the information necessary for translation tonon-human primates and ultimately to man. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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