| Literature DB >> 24900700 |
Mathieu Dubernet1, Nicolas Duguet2, Lionel Colliandre2, Christophe Berini2, Stéphane Helleboid1, Marilyne Bourotte1, Matthieu Daillet2, Lucie Maingot2, Sébastien Daix1, Jean-François Delhomel1, Luc Morin-Allory2, Sylvain Routier2, Robert Walczak1.
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.Entities:
Keywords: Biginelli; NR1F1; RORα; SAR; agonist; docking
Year: 2013 PMID： 24900700 PMCID： PMC4027490 DOI： 10.1021/ml300471d
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345