1 research outputs found
Identification of New Nonsteroidal RORα Ligands; Related Structure–Activity Relationships and Docking Studies
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 <b>8</b> and <b>9</b> 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 <b>8</b> (<i>S</i>-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