Design, structure activity relationships and X-Ray co-crystallography of non-steroidal LXR agonists

Area of Science:

• Medicinal Chemistry
• Molecular Pharmacology
• Structural Biology

Background:

• Liver X Receptors (LXR) alpha and beta are type II nuclear receptors that heterodimerize with Retinoid X Receptor (RXR).
• LXRalpha is primarily expressed in the liver, intestine, adipose tissue, and macrophages, while LXRbeta is ubiquitously expressed.
• LXR agonists regulate gene expression upon binding to their cognate receptors.

Purpose of the Study:

• To review medicinal chemistry strategies for optimizing novel non-steroidal Liver X Receptor (LXR) agonists.
• To analyze structural features critical for LXR ligand binding using structure-activity relationship (SAR) and X-ray crystallography data.
• To explore the potential of LXRbeta-selective compounds for improved therapeutic outcomes by dissociating beneficial and adverse effects of LXR agonism.

Main Methods:

• Review of reported medicinal chemistry efforts targeting non-steroidal LXR agonists.
• Analysis of structure-activity relationship (SAR) data from LXR assays.
• Examination of X-ray co-crystallographic data of LXR ligands bound to the LXR ligand-binding domain (LBD).

Main Results:

• Identification of key structural interactions required for LXR binding and agonist activity across different chemotype classes.
• Demonstration of modest LXRalpha selectivity in some compounds, but significant challenges in developing potent LXRbeta-selective agonists.
• SAR and crystallographic data suggest rational design of LXRbeta-selective compounds is complex.

Conclusions:

• Developing potent and selective LXRbeta agonists remains a significant medicinal chemistry challenge.
• Understanding structural determinants of LXR binding is crucial for designing targeted therapies.
• LXRbeta selectivity may offer a therapeutic advantage by separating desired lipid-modulating effects from potential adverse effects.