Discovery and structure–activity relationships of ent-Kaurene diterpenoids as potent and selective 11β-HSD1 inhibitors: Potential impact in diabetes

•The discovery of ent-kaurane diterpenoids 1b as novel selective 11β-HSD1 inhibitors was reported.•Thirty-six structurally diverse analogs derived from the leads 1b and 2 were designed and synthesized.•The potency and selectivity of the derivatives were evaluated using SPA.•Seven urea derivatives exhibited significantly improved potency and selectivity.

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.

Graphical abstractThirty-six structurally diverse analogs derived from ent-kaurane diterpenoids were designed and synthesized as selective 11β-HSD1 inhibitors. The 2D and 3D binding schemes of complex 19a/human 11β-HSD1 were also generated.Figure optionsDownload full-size imageDownload as PowerPoint slide