Design and synthesis of spirocyclic ligands of glucocorticoid receptors

• DOI: 10.1016/j.tet.2018.02.030
• Publication Date: 2018-02-17T17:28:11Z
• Authors: Eduard Badarau; Frédéric Robert; Stéphane Massip; Florian Jakob; Simon Lucas; Sven Frormann; Léon Ghosez
• Keywords: Diastereomer

Abstract Spirocyclic indazoles were designed as potential ligands for the glucocorticoid receptors (GRs). A short and efficient synthetic sequence was developed allowing the preparation of pure diastereomeric spirocyclic analogs of fluorocortivazol. Our studies also revealed a new application of Burgess reagent leading to a ring expansion. The structures and conformations of several key intermediates and products were confirmed by single crystal X-ray diffraction analysis. Conformational assignments were also supported by DFT calculations. As a proof of concept we tested the affinity of diastereomeric compounds 13b and 14b for the GRs. Rewardingly, it was found that 14b showed a promising IC50 of 27 nM.