Pyrazole[3,4-e][1,4]thiazepin-7-one derivatives as a novel class of Farnesoid X Receptor (FXR) agonists |
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Authors: | Marinozzi Maura Carotti Andrea Sansone Emanuele Macchiarulo Antonio Rosatelli Emiliano Sardella Roccaldo Natalini Benedetto Rizzo Giovanni Adorini Luciano Passeri Daniela De Franco Francesca Pruzanski Mark Pellicciari Roberto |
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Affiliation: | Dipartimento di Chimica e Tecnologia del Farmaco, Università di Perugia, Via del Liceo, I-06123 Perugia, Italy. maura@chimfarm.unipg.it |
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Abstract: | A virtual screening procedure was applied to the discovery of structurally diverse non-steroidal Farnesoid X Receptor (FXR) agonists. From 117 compounds selected by virtual screening, a total of 47 compounds were found to be FXR agonists, with 34 of them showing activity below a concentration of 20 μM. 1H-Pyrazole[3,4-e][1,4]thiazepin-7-one-based hit compound 7 was chosen for hit-to-lead optimization. A large number of 1H-pyrazole[3,4-e][1,4]thiazepin-7-one derivatives was designed, synthesized, and evaluated by a cell-based luciferase transactivation assay for their agonistic activity against FXR. Most of them exhibited low micromolar range of potency and very high efficacy. |
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