title: Discovery and structure-activity relationships of ent-Kaurene diterpenoids as potent and selective 11β-HSD1 inhibitors: potential impact in diabetes.
abstract: The biological screening of a collection of nature occurring diterpenoids against 11β-HSD1 resulted in the discovery of the lead compound 1b, which pointed to the therapeutic potential for type 2 diabetes. Subsequently, an optimization project was initiated. Starting from compound 1b and its counterpart 2, the hemi-synthesis was performed on kaurenic acid scaffolds yielding 36 derivatives. Further evaluations on both human and mouse 11β-HSD revealed that seven urea derivatives exhibited significant improved potency and selectivity. Especially, the urea 19a has an IC50 (human 11β-HSD1) = 9.4 nM and selectivity index (human 11β-HSD) > 10,649. The 2D and 3D binding models of the complex 19a/11β-HSD1 were generated using docking simulations. Based on the results, the structural-activity relationships (SARs) of compounds 1b and 2 were also discussed.
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650204, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Deng
authors.forename: Yu
authors.initials: Y
authors.lastname: Shen
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: Juan
authors.initials: J
authors.lastname: He
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhao
authors.forename: Li-Yan
authors.initials: LY
authors.lastname: Peng
authors.forename: Ying
authors.initials: Y
authors.lastname: Leng
authors.forename: Qin-Shi
authors.initials: QS
authors.lastname: Zhao
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D004224:Diterpenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D013329:Structure-Activity Relationship
chemical_list: D004224:Diterpenes; D004791:Enzyme Inhibitors; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1
keywords: Diabetes; Selective 11β-HSD1 inhibitors; Structure–activity relationship studies; Urea derivatives; ent-Kaurene diterpenoids