title: Asymmetric synthesis of the four diastereoisomers of a novel non-steroidal farnesoid X receptor (FXR) agonist: role of the chirality on the biological activity.
abstract: An asymmetric synthetic strategy was designed for the preparation of the four possible diastereoisomers of 3,6-dimethyl-1-(2-methylphenyl)-4-(4-phenoxyphenyl)-4,8-dihydro-1H-pyrazolo[3,4-e][1,4]thiazepin-7-one, a non-steroidal FXR agonist, we recently discovered following a virtual screening approach. The results obtained from an AlphaScreen assay clearly demonstrated that only the isomer endowed with 4R,6S absolute configuration is responsible for the biological activity. A deep investigation of the different putative binding modes adopted by these enantiomerically pure ligands using computational modeling studies confirmed the enantioselectivity of FXR towards this class of molecules.
authors.affiliation: Dipartimento di Chimica e Tecnologia del Farmaco, Università di Perugia, Via del Liceo, 1-06123 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: Roccaldo
authors.initials: R
authors.lastname: Sardella
authors.forename: Federica
authors.initials: F
authors.lastname: Buonerba
authors.forename: Federica
authors.initials: F
authors.lastname: Ianni
authors.forename: Benedetto
authors.initials: B
authors.lastname: Natalini
authors.forename: Daniela
authors.initials: D
authors.lastname: Passeri
authors.forename: Giovanni
authors.initials: G
authors.lastname: Rizzo
authors.forename: Roberto
authors.initials: R
authors.lastname: Pellicciari
mesh_terms: D006801:Humans; D011485:Protein Binding; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D013237:Stereoisomerism; D013841:Thiazepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D011720:Pyrazoles; D018160:Receptors, Cytoplasmic and Nuclear; D013841:Thiazepines; D000099150:Receptor, Farnesoid X-Activated