Design, structure activity relationships and X-Ray co-crystallography of non-steroidal LXR agonists.
Curr Med Chem
; 15(2): 195-209, 2008.
Article
en En
| MEDLINE
| ID: mdl-18220775
ABSTRACT
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.
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Bases de datos:
MEDLINE
Asunto principal:
Receptores Citoplasmáticos y Nucleares
/
Proteínas de Unión al ADN
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Curr Med Chem
Asunto de la revista:
QUIMICA
Año:
2008
Tipo del documento:
Article
País de afiliación:
Reino Unido