Carbamate and Sulfamate Bioisosteres of N,N-Dimethyl-3β-Hydroxycholenamide as Ligands of the Liver X Receptors.

Abstract

Modulating activity of liver X receptors (LXR) has garnered increasing interest, as its principal endogenous ligands, oxysterols, are implicated in diverse disorders, including atherosclerosis and metabolic syndrome. N,N-dimethyl-3β-hydroxycholenamide (DMHCA, 1), a synthetic LXR ligand, exhibits promising features and a favorable safety profile without elevating triglycerides or inducing hepatic steatosis. Here, we describe the synthesis, biological profile, and mode of action against LXR isoforms, of two novel side chain bioisosteric analogues of DMHCA (1) where the dimethylamide was replaced by a N,N-dimethyl carbamate (2) or sulfamate (3). These compounds were obtained in good yields via a simple synthetic sequence starting from stigmasterol, a readily available phytosterol byproduct from the soybean industry. Both analogues 2 and 3 exhibited agonistic activity comparable to DMHCA (1) in luciferase reporter assays in human HEK-293 T cells, although sulfamate (3) proved to be more effective (LXRα/1 pEC₅₀ = 6.4; LXRβ/1 pEC₅₀ = 6.4; LXRα/2 pEC₅₀ = 5.3; LXRβ/2 pEC₅₀ = 5.6; LXRα/3 pEC₅₀ = 6.0; LXRβ/3 pEC₅₀ = 6.1). Molecular dynamics simulations of the LXRβ/ligand complexes confirmed a stable binding mode consistent with the dose-response data in all cases. The results set the foundation for developing novel analogues based on these compounds, particularly with sulfamate (3).