Identification of New Nonsteroidal ROR伪 Ligands; Related Structure鈥揂ctivity Relationships and Docking Studies
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- 作者：Mathieu Dubernet ; Nicolas Duguet ; Lionel Colliandre ; Christophe Berini ; St茅phane Helleboid ; Marilyne Bourotte ; Matthieu Daillet ; Lucie Maingot ; S茅bastien Daix ; Jean-Fran莽ois Delhomel ; Luc Morin-Allory ; Sylvain Routier ; Robert Walczak
- 刊名：ACS Medicinal Chemistry Letters
- 出版年：2013
- 出版时间：June 13, 2013
- 年：2013
- 卷：4
- 期：6
- 页码：504-508
- 全文大小：306K
- 年卷期：v.4,no.6(June 13, 2013)
- ISSN：1948-5875
文摘
A high throughput screen was developed to identify novel, nonsteroidal ROR伪 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鈥揳ctivity 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伪 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伪 physiopathology.