Non-secosteroidal Ligands and Modulators

Publisher Summary This chapter provides an understanding of the identification, synthesis, biological, and pharmacological activities of non-secosteroidal ligands and modulators that are capable of binding in the traditional ligand-binding pocket of vitamin D receptor (VDR) to manipulate its physiologic and homeostatic functions in the various target tissues where it is expressed. The two main reasons for pursuing the design and development of novel non-secosteroidal ligands include the need for new and effective pharmacological agents for human disease treatment as well as the identification of research tools to further elucidate the biological function of vitamin D and VDR. The unique structural features of nonsecosteroidal ligands may afford advantageous properties that are inherently different from the liabilities surrounding 1α,25(OH) 2 D 3 or its secosteroidal analogs. These properties include altered DBP binding, reduced 24-hydroxylase metabolism, distinct VDR modulating behavior, or enhanced pharmacokinetic and pharmacodynamic profiles. Five classes of compounds that can be chemically classified as non-secosteroids include molecules based on a diarylmethane chemical scaffold (LG190119, VDRM-2), C/D ring-modified scaffolds, bis- and tris-aromatic triols (CD4420), podocarpic acid derivative (VDRL-1), and steroidal compounds such as the secondary bile acid lithocholic acid and its derivatives. The structure and chemistry of these molecules are described in the chapter.