4C7J

11b-Hydroxysteroid Dehydrogenase Type I in complex with inhibitor

4C7J の概要

• エントリーDOI: 10.2210/pdb4c7j/pdb
• 関連するPDBエントリー: 4C7K
• 分子名称: CORTICOSTEROID 11-BETA-DEHYDROGENASE ISOZYME 1, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 4-cyclopropyl-2-(2-hydroxyethyloxy)-N-[(1S,3R)-5-oxidanyl-2-adamantyl]-1,3-thiazole-5-carboxamide, ... (4 entities in total)
• 機能のキーワード: oxidoreductase, cns penetration, structure-based design
• 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: 4
• 化学式量合計: 123081.14

構造登録者

Goldberg, F.W.,Dossetter, A.G.,Scott, J.S.,Robb, G.R.,Boyd, S.,Groombridge, S.D.,Kemmitt, P.D.,Sjogren, T.,Morentin Gutierrez, P.,de Schoolmeester, J.,Swales, J.G.,Turnbull, A.V.,Wild, M.J. (登録日: 2013-09-23, 公開日: 2014-09-03, 最終更新日: 2024-05-08)

主引用文献

Goldberg, F.W.,Dossetter, A.G.,Scott, J.S.,Robb, G.R.,Boyd, S.,Groombridge, S.D.,Kemmitt, P.D.,Sjogren, T.,Gutierrez, P.M.,Deschoolmeester, J.,Swales, J.G.,Turnbull, A.V.,Wild, M.J.
Optimization of Brain Penetrant 11Beta-Hydroxysteroid Dehydrogenase Type I Inhibitors and in Vivo Testing in Diet- Induced Obese Mice.
J.Med.Chem., 57:970-, 2014

PubMed Abstract: 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) has been widely considered by the pharmaceutical industry as a target to treat metabolic syndrome in type II diabetics. We hypothesized that central nervous system (CNS) penetration might be required to see efficacy. Starting from a previously reported pyrimidine compound, we removed hydrogen-bond donors to yield 3, which had modest CNS penetration. More significant progress was achieved by changing the core to give 40, which combines good potency and CNS penetration. Compound 40 was dosed to diet-induced obese (DIO) mice and gave excellent target engagement in the liver and high free exposures of drug, both peripherally and in the CNS. However, no body weight reduction or effects on glucose or insulin were observed in this model. Similar data were obtained with a structurally diverse thiazole compound 51. This work casts doubt on the hypothesis that localized tissue modulation of 11β-HSD1 activity alleviates metabolic syndrome.

PubMed: 24422550
DOI: 10.1021/JM4016729

実験手法

X-RAY DIFFRACTION (2.16 Å)