title: Identification of New Nonsteroidal RORα Ligands; Related Structure-Activity Relationships and Docking Studies.
abstract: A high throughput screen was developed to identify novel, nonsteroidal RORα agonists. Among the validated hit compounds, the 4-(4-(benzyloxy)phenyl)-5-carbonyl-2-oxo-1,2,3,4-tetrahydropyrimidine scaffold was the most prominent. Among the numerous analogues tested, compounds 8 and 9 showed the highest activity. Key structure-activity relationships (SAR) were established, where benzyl and urea moieties were both identified as very important elements to maintain the activity. Most notably, the SAR were consistent with the binding mode of the compound 8 (S-isomer) in the RORα docking model that was developed in this program. As predicted by the model, the urea moiety is engaged in the formation of key hydrogen bonds with the backbone of Tyr380 and Asp382. The benzyl group is located in a wide hydrophobic pocket. The structural relationships reported in this letter will help in further optimization of this compound series and will provide novel synthetic probes helpful for elucidation of complex RORα physiopathology.
authors.affiliation: Genfit SA , 885 Av. E. Avinée, 59120 Loos, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Dubernet
authors.affiliation: Institut de Chimie Organique et Analytique (ICOA), Université d'Orléans , UMR CNRS 7311, rue de Chartres, BP 6759, 45067 Orléans, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Duguet
authors.affiliation: Institut de Chimie Organique et Analytique (ICOA), Université d'Orléans , UMR CNRS 7311, rue de Chartres, BP 6759, 45067 Orléans, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Colliandre
authors.affiliation: Institut de Chimie Organique et Analytique (ICOA), Université d'Orléans , UMR CNRS 7311, rue de Chartres, BP 6759, 45067 Orléans, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Berini
authors.affiliation: Genfit SA , 885 Av. E. Avinée, 59120 Loos, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Helleboid
authors.affiliation: Genfit SA , 885 Av. E. Avinée, 59120 Loos, France.
authors.forename: Marilyne
authors.initials: M
authors.lastname: Bourotte
authors.affiliation: Institut de Chimie Organique et Analytique (ICOA), Université d'Orléans , UMR CNRS 7311, rue de Chartres, BP 6759, 45067 Orléans, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Daillet
authors.affiliation: Institut de Chimie Organique et Analytique (ICOA), Université d'Orléans , UMR CNRS 7311, rue de Chartres, BP 6759, 45067 Orléans, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Maingot
authors.affiliation: Genfit SA , 885 Av. E. Avinée, 59120 Loos, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Daix
authors.affiliation: Genfit SA , 885 Av. E. Avinée, 59120 Loos, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Delhomel
authors.affiliation: Institut de Chimie Organique et Analytique (ICOA), Université d'Orléans , UMR CNRS 7311, rue de Chartres, BP 6759, 45067 Orléans, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Morin-Allory
authors.affiliation: Institut de Chimie Organique et Analytique (ICOA), Université d'Orléans , UMR CNRS 7311, rue de Chartres, BP 6759, 45067 Orléans, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Routier
authors.affiliation: Genfit SA , 885 Av. E. Avinée, 59120 Loos, France.
authors.forename: Robert
authors.initials: R
authors.lastname: Walczak
keywords: Biginelli; NR1F1; RORα; SAR; agonist; docking