Side-Chain Modified Ergosterol and Stigmasterol Derivatives as Liver X Receptor Agonists

A series of stigmasterol and ergosterol derivatives, characterized by the presence of oxygenated functions at C-22 and/or C-23 positions, were designed as potential liver X receptor (LXR) agonists. The absolute configuration of the newly created chiral centers was definitively assigned for all the corresponding compounds. Among the 16 synthesized compounds, 21, 27, and 28 were found to be selective LXR alpha agonists, whereas 20, 22, and 25 showed good selectivity for the LXR beta isoform. In particular, 25 showed the same degree of potency as 22R-HC (3) at LXR beta, while it was virtually inactive at LXR alpha (EC50 = 14.51 mu M). Interestingly, 13, 19, 20, and 25 showed to be LXR target gene-selective modulators, by strongly inducing the expression of ABCA1, while poorly or not activating the lipogenic genes SREBP1 and SCD1 or FASN, respectively.