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Identification of New Nonsteroidal ROR? Ligands; Related Structure-Activity Relationships and Docking Studies.

ABSTRACT: A high throughput screen was developed to identify novel, nonsteroidal ROR? 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 ROR? 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 ROR? physiopathology.

SUBMITTER: Dubernet M 

PROVIDER: S-EPMC4027490 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Identification of New Nonsteroidal RORα Ligands; Related Structure-Activity Relationships and Docking Studies.

Dubernet Mathieu M   Duguet Nicolas N   Colliandre Lionel L   Berini Christophe C   Helleboid Stéphane S   Bourotte Marilyne M   Daillet Matthieu M   Maingot Lucie L   Daix Sébastien S   Delhomel Jean-François JF   Morin-Allory Luc L   Routier Sylvain S   Walczak Robert R  

ACS medicinal chemistry letters 20130410 6

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  ...[more]

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