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

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.