RESUMO
Methodology to prepare 8-amido-2-amino-1,2,3,4-tetrahydro-2-dibenzofurans, analogues with a fluorine substituent incorporated in the 6-, 7-, and 9-positions, and a difluorinated analogue with fluorines in the 6- and 9-positions is described. The tetrahydrodibenzofuran ring systems are prepared by acid-catalyzed [3,3]-sigmatropic rearrangement of O-aryloximes. Regioselective reactions to prepare the requisite O-aryloxime intermediates from commercially available fluorobenzene derivatives are discussed.
Assuntos
Técnicas de Química Combinatória , Furanos/síntese química , Hidrocarbonetos Fluorados/síntese química , Oximas/química , Carbazóis/química , Catálise , Cromatografia Líquida de Alta Pressão , Fluorbenzenos/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Serotonina/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Fenofibrate is clinically successful in treating hypertriglyceridemia and mixed hyperlipidemia presumably through peroxisome proliferator-activated receptor alpha (PPARalpha)-dependent induction of genes that control fatty acid beta-oxidation. Lipid homeostasis and cholesterol metabolism also are regulated by the nuclear oxysterol receptors, liver X receptors alpha and beta (LXRalpha and LXRbeta). Here we show that fenofibrate ester, but not fenofibric acid, functions as an LXR antagonist by directly binding to LXRs. Likewise, ester forms, but not carboxylic acid forms, of other members of the fibrate class of molecules antagonize the LXRs. The fibrate esters display greater affinity for LXRs than the corresponding fibric acids have for PPARalpha. Thus, these two nuclear receptors display a degree of conservation in their recognition of ligands; yet, the acid/ester moiety acts as a chemical switch that determines PPARalpha versus LXR specificity. Consistent with its LXR antagonistic activity, fenofibrate potently represses LXR agonist-induced transcription of hepatic lipogenic genes. Surprisingly, fenofibrate does not repress LXR-induced transcription of various ATP-binding cassette transporters either in liver or in macrophages, suggesting that fenofibrate manifests variable biocharacter in the context of differing gene promoters. These findings provide not only an unexpected mechanism by which fenofibrate inhibits lipogenesis but also the basis for examination of the pharmacology of an LXR ligand in humans.
