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PDBsum entry 4zgx
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Oxidoreductase
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PDB id
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4zgx
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References listed in PDB file
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Key reference
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Title
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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.
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Authors
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R.E.Martin,
J.D.Aebi,
B.Hornsperger,
H.J.Krebs,
B.Kuhn,
A.Kuglstatter,
A.M.Alker,
H.P.Märki,
S.Müller,
D.Burger,
G.Ottaviani,
W.Riboulet,
P.Verry,
X.Tan,
K.Amrein,
A.V.Mayweg.
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Ref.
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J Med Chem, 2015,
58,
8054-8065.
[DOI no: ]
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PubMed id
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Abstract
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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.
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