Dal Pra, M;
Carta, D;
Szabadkai, G;
Suman, M;
Frion-Herrera, Y;
Paccagnella, N;
Castellani, G;
... Ferlin, MG; + view all
(2018)
Targeting RORs nuclear receptors by novel synthetic steroidal inverse agonists for autoimmune disorders.
Bioorganic & Medicinal Chemistry
, 26
(8)
pp. 1686-1704.
10.1016/j.bmc.2018.02.018.
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Abstract
Designing novel inverse agonists of NR RORγt still represents a challenge for the pharmaceutical community to develop therapeutics for treating immune diseases. By exploring the structure of NRs natural ligands, the representative arotenoid ligands and RORs specific ligands share some chemical homologies which can be exploited to design a novel molecular structure characterized by a polycyclic core bearing a polar head and a hydrophobic tail. Compound MG 2778 (8), a cyclopenta[a]phenantrene derivative, was identified as lead compound which was chemically modified at position 2 in order to obtain a small library for preliminary SARs. Cell viability and estrogenic activity of compounds 7, 8, 19a, 30, 31 and 32 were evaluated to attest selectivity. The selected 7, 8, 19a and 31 compounds were assayed in a Gal4 UAS-Luc co-transfection system in order to determine their ability to modulate RORγt activity in a cellular environment. They were evaluated as inverse agonists taken ursolic acid as reference compound. The potency of compounds was lower than that of ursolic acid, but their efficacy was similar. Compound 19a was the most active, significantly reducing RORγt activity at low micromolar concentrations.
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