Structural requirements of cholenamide derivatives as the LXR ligands.

A study of the structural requirements of cholic acid derivatives as liver X receptor (LXR) ligands was performed. A model of cholenamide derivative 1 complexed with LXR showed that the C24 carbonyl oxygen forms a hydrogen bond with His435 located close to Trp457. The N,N-dimethyl group is located in a hydrophobic pocket. Based on these data, we designed compounds with high affinity for LXRs. Cholenamide derivatives 1-11 were synthesized from 3ß-acetyl-Δ5-cholenic acid 20, and lactams 12-19 were synthesized from alcohol 25. Tertiary amides 3 and 4 showed higher activity in reporter assays, and compounds with hydrophobic residues exhibited the highest activity of all derivatives. The stereochemistry at C23 was found to be an important determinant of EC50 and gene transactivation, as each isomer exhibited different activity.