title: Pyrazole[3,4-e][1,4]thiazepin-7-one derivatives as a novel class of Farnesoid X Receptor (FXR) agonists.
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.
authors.affiliation: Dipartimento di Chimica e Tecnologia del Farmaco, Università di Perugia, Via del Liceo, I-06123 Perugia, Italy. maura@chimfarm.unipg.it
authors.forename: Maura
authors.initials: M
authors.lastname: Marinozzi
authors.forename: Andrea
authors.initials: A
authors.lastname: Carotti
authors.forename: Emanuele
authors.initials: E
authors.lastname: Sansone
authors.forename: Antonio
authors.initials: A
authors.lastname: Macchiarulo
authors.forename: Emiliano
authors.initials: E
authors.lastname: Rosatelli
authors.forename: Roccaldo
authors.initials: R
authors.lastname: Sardella
authors.forename: Benedetto
authors.initials: B
authors.lastname: Natalini
authors.forename: Giovanni
authors.initials: G
authors.lastname: Rizzo
authors.forename: Luciano
authors.initials: L
authors.lastname: Adorini
authors.forename: Daniela
authors.initials: D
authors.lastname: Passeri
authors.forename: Francesca
authors.initials: F
authors.lastname: De Franco
authors.forename: Mark
authors.initials: M
authors.lastname: Pruzanski
authors.forename: Roberto
authors.initials: R
authors.lastname: Pellicciari
mesh_terms: D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D020869:Gene Expression Profiling; D056945:Hep G2 Cells; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D011720:Pyrazoles / Q000737:chemistry*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D013841:Thiazepines / Q000138:chemical synthesis* / Q000494:pharmacology*; D014584:User-Computer Interface; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D008156:Luciferases; D011720:Pyrazoles; D018160:Receptors, Cytoplasmic and Nuclear; D013841:Thiazepines; D000099150:Receptor, Farnesoid X-Activated; C031280:pyrazole