4P38

Human 11beta-Hydroxysteroid Dehydrogenase Type 1 in complex with AZD8329

4P38 の概要

• エントリーDOI: 10.2210/pdb4p38/pdb
• 関連するPDBエントリー: 4HFR
• 分子名称: Corticosteroid 11-beta-dehydrogenase isozyme 1, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]benzoic acid, ... (5 entities in total)
• 機能のキーワード: alpha beta, rossmann fold, nadp, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Endoplasmic reticulum membrane ; Single-pass type II membrane protein : P28845
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 60838.64

構造登録者

Ogg, D.,Hargreaves, D.,Gerhardt, S. (登録日: 2014-03-06, 公開日: 2014-04-30, 最終更新日: 2024-02-28)

主引用文献

Scott, J.S.,deSchoolmeester, J.,Kilgour, E.,Mayers, R.M.,Packer, M.J.,Hargreaves, D.,Gerhardt, S.,Ogg, D.J.,Rees, A.,Selmi, N.,Stocker, A.,Swales, J.G.,Whittamore, P.R.
Novel acidic 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) inhibitor with reduced acyl glucuronide liability: the discovery of 4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]benzoic acid (AZD8329).
J.Med.Chem., 55:10136-10147, 2012

PubMed Abstract: Inhibition of 11β-HSD1 is viewed as a potential target for the treatment of obesity and other elements of the metabolic syndrome. We report here the optimization of a carboxylic acid class of inhibitors from AZD4017 (1) to the development candidate AZD8329 (27). A structural change from pyridine to pyrazole together with structural optimization led to an improved technical profile in terms of both solubility and pharmacokinetics. The extent of acyl glucuronidation was reduced through structural optimization of both the carboxylic acid and amide substituents, coupled with a reduction in lipophilicity leading to an overall increase in metabolic stability.

PubMed: 23088558
DOI: 10.1021/jm301252n

実験手法

X-RAY DIFFRACTION (2.8 Å)