title: 1,1-Dioxo-5,6-dihydro-[4,1,2]oxathiazines, a novel class of 11ß-HSD1 inhibitors for the treatment of diabetes.
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.
authors.affiliation: Sanofi Deutschland GmbH, R&D, Industriepark Höchst, 65926 Frankfurt am Main, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Böhme
authors.forename: Christian K
authors.initials: CK
authors.lastname: Engel
authors.forename: Géraldine
authors.initials: G
authors.lastname: Farjot
authors.forename: Stefan
authors.initials: S
authors.lastname: Güssregen
authors.forename: Torsten
authors.initials: T
authors.lastname: Haack
authors.forename: Georg
authors.initials: G
authors.lastname: Tschank
authors.forename: Kurt
authors.initials: K
authors.lastname: Ritter
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors*; D000818:Animals; D001665:Binding Sites; D003920:Diabetes Mellitus / Q000188:drug therapy*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004795:Enzyme Stability; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013843:Thiazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D013843:Thiazines; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1
keywords: 1,1-Dioxo-5,6-dihydro-[4,1,2]oxathiazine; 11β-HSD1 inhibitors; 11β-Hydroxysteroid dehydrogenase type 1; Diabetes