4ZGX

Structure of aldosterone synthase (CYP11B2) in complex with (+)-(R)-N-(4-(4-chloro-3-fluorophenyl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide

Summary for 4ZGX

• Entry DOI: 10.2210/pdb4zgx/pdb
• Descriptor: Cytochrome P450 11B2, mitochondrial, PROTOPORPHYRIN IX CONTAINING FE, N-[(8R)-4-(4-chloro-3-fluorophenyl)-5,6,7,8-tetrahydroisoquinolin-8-yl]propanamide, ... (4 entities in total)
• Functional Keywords: cytochrome p450, cyp11b2, aldosterone synthase, oxidoreductase
• Biological source: Homo sapiens (Human)
• Cellular location: Mitochondrion membrane: P19099
• Total number of polymer chains: 12
• Total formula weight: 685632.23

Authors

Kuglstatter, A.,Joseph, C. (deposition date: 2015-04-24, release date: 2015-10-07, Last modification date: 2024-05-01)

Primary citation

Martin, R.E.,Aebi, J.D.,Hornsperger, B.,Krebs, H.J.,Kuhn, B.,Kuglstatter, A.,Alker, A.M.,Marki, H.P.,Muller, S.,Burger, D.,Ottaviani, G.,Riboulet, W.,Verry, P.,Tan, X.,Amrein, K.,Mayweg, A.V.
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.
J.Med.Chem., 58:8054-8065, 2015

PubMed 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.

PubMed: 26403853
DOI: 10.1021/acs.jmedchem.5b00851

Experimental method

X-RAY DIFFRACTION (3.2 Å)