Identification of a Privileged Scaffold for Inhibition of Sterol Transport Proteins through the Synthesis and Ring Distortion of Diverse, Pseudo-Natural Products

Sterol transport proteins mediate intracellular sterol transport, organelle contact sites, and lipid metabolism. Despite their importance, the similarities in their sterol-binding domains have made the identification of selective modulators difficult. Herein we report a combination of different compound library synthesis strategies to prepare a cholic acid-inspired compound collection for the identification of potent and selective inhibitors of sterol transport proteins. The fusion of a primary sterol scaffold with a range of different fragments found in natural products followed by various ring distortions allowed the synthesis of diverse sterol-inspired compounds. This led to the identification of a complex and three-dimensional spirooxepinoindole as a privileged scaffold for sterol transport proteins. With careful optimization of the scaffold, the selectivity could be directed toward a single transporter, as showcased by the development of a potent and selective Aster-A inhibitor. We suggest that the combination of different design strategies is generally applicable for the identification of potent and selective bioactive compounds with drug-like properties.