Synthesis and structure activity relationship of the first class of LXR inverse agonists.
Bioorg Chem
; 119: 105540, 2022 02.
Article
em En
| MEDLINE
| ID: mdl-34902646
ABSTRACT
Liver X Receptors (LXRs) are members of the nuclear receptor family, and they play significant role in lipid and cholesterol metabolism. Moreover, they are key regulators of several inflammatory pathways. Pharmacological modulation of LXRs holds great potential in treatment of metabolic diseases, neurodegenerative diseases, and cancer. We were the first group to identify LXR inverse agonists SR9238 (6) and SR9243 (7) and demonstrate their potential utility in treating liver diseases and cancer. Here, we present the results of structure-activity relationship (SAR) studies, based around SR9238 (6) and SR9243 (7). This study led to identification of 16, 17, 19, and 38, which were more potent inverse agonists than SR9238 (6) and SR9243 (7) and inhibited expression of the fatty acid synthase gene in DU145 cells. We previously demonstrated that inhibition of FASN is correlated to the anticancer activity of SR9243 (7) and this suggests that new inverse agonists have great potential as anticancer agents. We identified compounds with distinct selectivity toward both LXR isoforms, which can be excellent tools to study the pharmacology of both isoforms. We employed molecular dynamic (MD) simulations to better understand the molecular mechanism underlying inverse agonist activity and to guide our future design.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Sulfonamidas
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Receptores X do Fígado
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Compostos Heterocíclicos de 4 ou mais Anéis
Limite:
Humans
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article