Design, synthesis, and structure-activity relationship of podocarpic acid amides as liver X receptor agonists for potential treatment of atherosclerosis.

A series of podocarpic acid amides were identified as potent agonists for Liver X receptor alpha and beta subtypes, which are members of a nuclear hormone receptor superfamily that are involved in the regulation of a variety of metabolic pathways including cholesterol metabolism. We recently reported podocarpic acid anhydride and imide dimers as potent LXR agonists. Through parallel organic synthesis, we rapidly identified a series of new podocarpate leads with stable structures exemplified by adamantyl- and phenylcyclohexylmethyl-podocarpic acid amides (14 and 18). Compound 18 exhibited LXRalpha/beta 50/20 nM (binding affinity) and 33.7/35.3-fold receptor inductions. Synthesis, SAR, and biological activities of new podocarpate analogs are discussed.

[1]  G. Rodan,et al.  NER, a new member of the gene family encoding the human steroid hormone nuclear receptor. , 1994, Gene.

[2]  D. Mangelsdorf,et al.  The liver X receptor gene team: Potential new players in atherosclerosis , 2002, Nature Medicine.

[3]  K. Umesono,et al.  LXR, a nuclear receptor that defines a distinct retinoid response pathway. , 1995, Genes & development.

[4]  Yu-Sheng Chao,et al.  Discovery and development of dimeric podocarpic acid leads as potent agonists of liver X receptor with HDL cholesterol raising activity in mice and hamsters. , 2005, Bioorganic & medicinal chemistry letters.

[5]  S. Kliewer,et al.  Structural requirements of ligands for the oxysterol liver X receptors LXRalpha and LXRbeta. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[6]  Gaochao Zhou,et al.  27-Hydroxycholesterol Is an Endogenous Ligand for Liver X Receptor in Cholesterol-loaded Cells* , 2001, The Journal of Biological Chemistry.

[7]  Y. Chao,et al.  A Novel Liver X Receptor Agonist Establishes Species Differences in the Regulation of Cholesterol 7α-Hydroxylase (CYP7a). , 2002, Endocrinology.

[8]  Timothy M. Willson,et al.  Activation of the Nuclear Receptor LXR by Oxysterols Defines a New Hormone Response Pathway* , 1997, The Journal of Biological Chemistry.

[9]  Jonathan D. Smith,et al.  Cyclic AMP Induces Apolipoprotein E Binding Activity and Promotes Cholesterol Efflux from a Macrophage Cell Line to Apolipoprotein Acceptors* , 1996, The Journal of Biological Chemistry.

[10]  D. Moller,et al.  A Potent Synthetic LXR Agonist Is More Effective than Cholesterol Loading at Inducing ABCA1 mRNA and Stimulating Cholesterol Efflux* , 2002, The Journal of Biological Chemistry.

[11]  D. Mangelsdorf,et al.  An oxysterol signalling pathway mediated by the nuclear receptor LXRα , 1996, Nature.

[12]  J. Capone,et al.  The Orphan Nuclear Hormone Receptor LXR Interacts with the Peroxisome Proliferator-activated Receptor and Inhibits Peroxisome Proliferator Signaling (*) , 1996, The Journal of Biological Chemistry.