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

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.

Nickel Chloride Hexahydrate Catalyzed Multicomponent Biginelli's Synthesis of 3,4‐Dihydropyrimidin‐2(1H)‐Ones and Thiones

“…Biginelli compounds 8a , 8j , and 8r have all the detail of the experiments (with different methods except our procedure), spectroscopic data and physical properties on published literature . 8c , 8g , 8i , 8l , 8m , 8n , and 8s only have Chemical Abstracts Service Registry number but no published sources of literature.…”

“…mp 183–185°C, (lit. mp 188–189°C). IR (ATR diamond) cm –1 : 3241, 3111, 2973, 1701, 1675, 1641, 1610, 1584, 1509, 1456.…”

Discovery and structural optimization of 4-(4-(benzyloxy)phenyl)-3,4-dihydropyrimidin-2(1H)-ones as RORc inverse agonists

“…In this paper, we report the discovery of novel 4-(4-(benzyloxy)phenyl)-3,4-dihydropyrimidin-2(1H)-ones as potent RORc inverse agonists. Compound 8 has been previously described as an agonist of RORa [23] . Considering the sequence and structural similarity of RORa and RORc and their crucial role in the development of Th17-related diseases, compound 8 was assessed for its inhibitory effect on RORc.…”

“…In this study, we try to develop new RORc inverse agonists starting from compound 8 which was identified as RORa agonist [23] . In order to predict RORc-8 binding modes, we analyzed known RORc-ligand complex structures.…”

Unusually large scalar coupling between geminal protons in a saturated pyrimidine

“…Pyrimidines and their derivatives are ubiquitous biomolecules found throughout nature. The well‐known DNA bases, thymine and cytosine, and the RNA base, uracil, are pyrimidines, and 1,2,3,4‐tetrahydropyrimidines are a class of molecules that have been recently investigated for their antimicrobial and anti‐inflammatory properties . In their ongoing efforts to develop catalytic cycloaddition processes, the Doyle group reported the synthesis of 2‐substituted 1,2,3,4‐tetrahydropyrimidines 3 by a Lewis acid‐catalyzed [4 + 2] aza‐cycloaddition between azadiene 1 and aldimines 2 (Scheme ) .…”