Design and synthesis of spirocyclic ligands of glucocorticoid receptors

Eduard Badarau (1) , Frédéric Robert (2) , Stéphane Massip (3) , Florian Jakob , Simon Lucas , Sven Frormann , Léon Ghosez (1)

1 IECB - Institut Européen de Chimie et Biologie
2 ISM - Institut des Sciences Moléculaires
3 Soutien à la Recherche de l'Institut Européen de Chimie Biologique

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.

Mots clés: Spirocycles; Benzopyrazole; Glucocorticoids; Burgess reagent

Domaines: Chimie organique

Eduard Badarau, Frédéric Robert, Stéphane Massip, Florian Jakob, Simon Lucas, et al.. Design and synthesis of spirocyclic ligands of glucocorticoid receptors. Tetrahedron, 2018, 74 (38), pp.5119-5128. ⟨10.1016/j.tet.2018.02.030⟩. ⟨hal-02378436⟩