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Deprecated: Implicit conversion from float 265.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 ACS+Med+Chem+Lett 2013 ; 4 (6): 504-8 Nephropedia Template TP
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Identification of New Nonsteroidal ROR? Ligands; Related Structure?Activity Relationships and Docking Studies #MMPMID24900700
Dubernet M; Duguet N; Colliandre L; Berini C; Helleboid S; Bourotte M; Daillet M; Maingot L; Daix S; Delhomel JF; Morin-Allory L; Routier S; Walczak R
ACS Med Chem Lett 2013[Jun]; 4 (6): 504-8 PMID24900700show ga
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.