1,1-Dioxo-5,6-dihydro-[4,1,2]oxathiazines, a novel class of 11β-HSD1 inhibitors for the treatment of diabetes

被引：19

作者：

Boehme, Thomas ^{[1
]}

Engel, Christian K. ^{[1
]}

Farjot, Geraldine ^{[2
]}

Guessregen, Stefan ^{[1
]}

Haack, Torsten ^{[1
]}

Tschank, Georg ^{[1
]}

Ritter, Kurt ^{[1
]}

机构：

[1] Sanofi Deutschland GmbH, R&D, D-65926 Frankfurt, Germany

[2] Sanofi R&D, F-91385 Chilly Mazarin, France

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2013年 / 23卷 / 16期

关键词：

11 beta-Hydroxysteroid dehydrogenase type 1; 11; beta-HSD1; inhibitors; Diabetes; 1,1-Dioxo-5,6-dihydro-[4,1,2]oxathiazine; 11-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE-1; N-(PYRIDIN-2-YL) ARYLSULFONAMIDE INHIBITORS; STRUCTURE-BASED DESIGN; SELECTIVE INHIBITORS; N-SULFONYLAMINES; DISCOVERY; POTENT; SAR;

D O I：

10.1016/j.bmcl.2013.05.102

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-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 11 beta-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. (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：4685 / 4691

页数：7

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