RESUMO
N,N-Dimethyl 3ß-hydroxychol-5-en-24-amide (DMHCA, 3) is the prototype of cholenamides, a class of steroidal LXR modulators characterized by the nucleus of Δ5-cholen-3ß-ol and the presence of an amide moiety at C-24. DMHCA (3) has been reported to act as a gene-selective modulator able to fully induce ABCA1 expression whilst poorly up-regulate the expression of FASN and SREBP-1α genes. With the aim to widen the limited structure-activity relationships of DMHCA (3), herein we describe the synthesis and the biological evaluation of nine novel derivatives, resulting from a) the homologation of DMHCA's side-chain to give N,N-dimethyl 3ß-hydroxy-24a-homochol-5-en-24a-amide (4); b) the distal branching of the side-chain of 3 and 4 by introducing an ethyl group at C-23 and C-24, respectively; c) the replacement of the dimethyl amide moiety of all the derivatives with a carboxylic acid function. While broadening the structure-activity relationships of the class of cholenamides, we were successful in the discovery of (24R)-N,N-dimethyl-24-ethyl-3ß-hydroxy-24a-homochol-5-en-24a-amide (6) as a novel LXR agonist with improved profile in term of selective gene modulation respect to the prototype DMHCA (3); indeed, 6 was able to up-regulate the expression of ABCA1 more than DMHCA (3), without to induce SREBP-1c, differently from DMHCA (3). Moreover, 6 induced the expression of FASN less than 3 and interestingly was a negative modulator towards SCD1 in contrast to DMHCA (3), which instead weakly induced the expression of this gene.