4ZGX

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

4ZGX の概要

• エントリーDOI: 10.2210/pdb4zgx/pdb
• 分子名称: 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)
• 機能のキーワード: cytochrome p450, cyp11b2, aldosterone synthase, oxidoreductase
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Mitochondrion membrane: P19099
• タンパク質・核酸の鎖数: 12
• 化学式量合計: 685632.23

構造登録者

Kuglstatter, A.,Joseph, C. (登録日: 2015-04-24, 公開日: 2015-10-07, 最終更新日: 2024-05-01)

主引用文献

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

実験手法

X-RAY DIFFRACTION (3.2 Å)