Structural highlights
Disease
[DHI1_HUMAN] Defects in HSD11B1 are a cause of cortisone reductase deficiency (CRD) [MIM:604931]. In CRD, activation of cortisone to cortisol does not occur, resulting in adrenocorticotropin-mediated androgen excess and a phenotype resembling polycystic ovary syndrome (PCOS).
Function
[DHI1_HUMAN] Catalyzes reversibly the conversion of cortisol to the inactive metabolite cortisone. Catalyzes reversibly the conversion of 7-ketocholesterol to 7-beta-hydroxycholesterol. In intact cells, the reaction runs only in one direction, from 7-ketocholesterol to 7-beta-hydroxycholesterol (By similarity).
Publication Abstract from PubMed
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 11beta-hydroxysteroid dehydrogenase type 1 (11beta-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.
1,1-Dioxo-5,6-dihydro-[4,1,2]oxathiazines, a novel class of 11ss-HSD1 inhibitors for the treatment of diabetes.,Bohme T, Engel CK, Farjot G, Gussregen S, Haack T, Tschank G, Ritter K Bioorg Med Chem Lett. 2013 Aug 15;23(16):4685-91. doi:, 10.1016/j.bmcl.2013.05.102. Epub 2013 Jun 11. PMID:23845218[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Bohme T, Engel CK, Farjot G, Gussregen S, Haack T, Tschank G, Ritter K. 1,1-Dioxo-5,6-dihydro-[4,1,2]oxathiazines, a novel class of 11ss-HSD1 inhibitors for the treatment of diabetes. Bioorg Med Chem Lett. 2013 Aug 15;23(16):4685-91. doi:, 10.1016/j.bmcl.2013.05.102. Epub 2013 Jun 11. PMID:23845218 doi:http://dx.doi.org/10.1016/j.bmcl.2013.05.102
