4K1L

4,4-Dioxo-5,6-dihydro-[1,4,3]oxathiazines, a novel class of 11 beta-HSD1 inhibitors for the treatment of diabetes

4K1L の概要

• エントリーDOI: 10.2210/pdb4k1l/pdb
• 分子名称: Corticosteroid 11-beta-dehydrogenase isozyme 1, (4aS,8aR)-N-cyclohexyl-4a,5,6,7,8,8a-hexahydro-4,1,2-benzoxathiazin-3-amine 1,1-dioxide, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (4 entities in total)
• 機能のキーワード: 11-beta-hydroxysteroid dehydrogenase 1, 11-dh, 11-beta-hsd1, short chain dehydrogenase, 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: 4
• 化学式量合計: 131474.74

構造登録者

Loenze, P.,Schimanski-Breves, S.,Von der Heyden, C.,Engel, C.K. (登録日: 2013-04-05, 公開日: 2014-04-09, 最終更新日: 2023-09-20)

主引用文献

Bohme, T.,Engel, C.K.,Farjot, G.,Gussregen, S.,Haack, T.,Tschank, G.,Ritter, K.
1,1-Dioxo-5,6-dihydro-[4,1,2]oxathiazines, a novel class of 11-HSD1 inhibitors for the treatment of diabetes.
Bioorg.Med.Chem.Lett., 23:4685-4691, 2013

PubMed Abstract: Racemic cis-1,1-dioxo-5,6-dihydro-[4,1,2]oxathiazine derivative 4a was isolated as an impurity in a sample of a hit from a HTS campaign on 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). After separation by chiral chromatography the 4a-S, 8a-R enantiomer of compound 4a was identified as the true, potent enzyme inhibitor. The cocrystal structure of 4a with human and murine 11ß-HSD1 revealed the unique binding mode of the oxathiazine series. SAR elucidation and optimization in regard to metabolic stability led to monocyclic tetramethyloxathiazines as exemplified by compound 21g.

PubMed: 23845218
DOI: 10.1016/j.bmcl.2013.05.102

実験手法

X-RAY DIFFRACTION (1.96 Å)