RESUMO
The Liver X Receptor (LXR) alpha and beta isoforms are members of the type II nuclear receptor family which function as a heterodimer with the Retinoid X Receptor (RXR). Upon agonist binding, the formation of the LXR/RXR heterodimer takes place and ultimately the regulation of a number of genes begins. The LXR isoforms share 77% sequence homology, with LXRalpha having highest expression in liver, intestine, adipose tissue, and macrophages and LXRbeta being ubiquitously expressed. The aim of this article is to review the reported medicinal chemistry strategies towards the optimisation of novel non-steroidal chemotypes as LXR agonists. An analysis of the structural features important for LXR ligand binding will be given, utilising both structural activity relationship data obtained from LXR assays as well as X-ray co-crystallographic data obtained with LXR ligands and the LXR ligand binding domain (LBD). The X-ray co-crystallographic data analysis will detail the key structural interactions required for LXR binding/agonist activity and reveal the differences observed between chemotype classes. It has been postulated that a LXRbeta selective compound may have a beneficial outcome on the lipid profile for a ligand by dissociating the favourable and unfavourable effects of LXR agonists. Whilst there have been a few examples of compounds showing a modest level of LXRalpha selectivity, obtaining a potent LXRbeta selective compound has been more challenging. Analysis of the SAR and X-ray co-crystallographic data suggests that the rational design of a LXRbeta selective compound will not be trivial.
Assuntos
Proteínas de Ligação a DNA/agonistas , Proteínas de Ligação a DNA/metabolismo , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/metabolismo , Abietanos/química , Abietanos/metabolismo , Abietanos/farmacologia , Animais , Benzilaminas/química , Benzilaminas/metabolismo , Benzilaminas/farmacologia , Cristalografia por Raios X , Proteínas de Ligação a DNA/química , Desenho de Fármacos , Humanos , Ligantes , Receptores X do Fígado , Maleimidas/química , Maleimidas/metabolismo , Maleimidas/farmacologia , Receptores Nucleares Órfãos , Fenantrenos/química , Fenantrenos/metabolismo , Fenantrenos/farmacologia , Propanóis/química , Propanóis/metabolismo , Propanóis/farmacologia , Isoformas de Proteínas , Quinolinas/química , Quinolinas/metabolismo , Quinolinas/farmacologia , Receptores Citoplasmáticos e Nucleares/química , Relação Estrutura-AtividadeAssuntos
Peso Corporal , Promoção da Saúde , Militares , Adulto , Feminino , Humanos , Masculino , Fatores Sexuais , Estados UnidosRESUMO
Evidence in the medical literature substantiating the effect of test diets on the outcome of specific diagnostic tests is scanty and, in some cases, controversial. It has been clearly demonstrated that some test diets definitely affect the outcomes of some diagnostic tests. Therefore, these diets should be effectively and consistently used. Medical professionals should be familiar with specific test diets. There should be systematic management regarding the content of instructions to the patient, who gives the instructions, and how follow-up is made on compliance with the test diet. Clinical dietitians should be versatile regarding all test diets that may influence diagnostic test outcome. All test diets in dietary manuals for which there is no medical basis for effectiveness should be eliminated.
