Discovery and development of dimeric podocarpic acid leads as potent agonists of liver X receptor with HDL cholesterol raising activity in mice and hamsters

Singh, Sheo B.; Ondeyka, John G.; Liu, Weiguo; Chen, Steve; Chen, Tom S.; Li, Xiaohua; Bouffard, Aileen; Dropinski, James F.; Jones, A. Brian; McCormick, Sherrie; Hayes, Nancy S.; Wang, Jianhua; Sharma, Neelam; MacNaul, Karen L.; Hernandez, Melba; Chao, Yu‐Sheng; Baffic, Joanne; Lam, My-Hanh; Burton, Charlotte; Sparrow, Carl P.; Menke, John

doi:10.1016/j.bmcl.2005.03.100

Cited by 23 publications

(13 citation statements)

References 12 publications

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“…The more stable and potent imide increases the total plasma cholesterol levels by 28% with concomitant increase of HDL-cholesterol by 22% and decreases the LDL by 11% in hamsters. Similar results were also observed in mice where HDL-cholesterol levels were increased by 19% [ 82 ].…”

Section: Ligands Of Liver X Receptorssupporting

confidence: 84%

Ligands of Therapeutic Utility for the Liver X Receptors

et al. 2017

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Liver X receptors (LXRs) have been increasingly recognized as a potential therapeutic target to treat pathological conditions ranging from vascular and metabolic diseases, neurological degeneration, to cancers that are driven by lipid metabolism. Amidst intensifying efforts to discover ligands that act through LXRs to achieve the sought-after pharmacological outcomes, several lead compounds are already being tested in clinical trials for a variety of disease interventions. While more potent and selective LXR ligands continue to emerge from screening of small molecule libraries, rational design, and empirical medicinal chemistry approaches, challenges remain in minimizing undesirable effects of LXR activation on lipid metabolism. This review provides a summary of known endogenous, naturally occurring, and synthetic ligands. The review also offers considerations from a molecular modeling perspective with which to design more specific LXRβ ligands based on the interaction energies of ligands and the important amino acid residues in the LXRβ ligand binding domain.

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Section: Ligands Of Liver X Receptorssupporting

confidence: 84%

Ligands of Therapeutic Utility for the Liver X Receptors

et al. 2017

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“…Apart from natural products, several synthetic or semisynthetic compounds have been developed that show agonistic properties toward LXRs, as, for example, acetyl podocarpic acid anhydride that has been developed as a semi-synthetic agonist derived from extracts of the mayapple (Singh et al 2005). Among all the compounds developed so far that show high affinity for LXRs, two nonsteroidal synthetic agonists, namely TO901317 (Schultz et al 2000) and GW3965 (Collins et al 2002), have been most widely used for in vitro and in vivo studies dissecting the roles of LXRs in cell biology and physiology.…”

Section: Roads To Lxr Activationmentioning

confidence: 99%

Biological Roles of Liver X Receptors in Immune Cells

Pascual-García

Valledor

2012

Arch. Immunol. Ther. Exp.

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Liver X receptors (LXRs) are members of the nuclear receptor superfamily that are activated by specific oxysterols. LXRs heterodimerize with retinoid X receptors to regulate positively the expression of a variety of target genes, many of which are involved in lipid and glucose metabolism. In the last few years, new targets of LXR activation have been identified with roles in the modulation of immune responses. Moreover, LXRs mediate repression of inflammatory pathways through mechanisms collectively known as transrepression. Here, we revise recent findings on the impact of LXR activation on immune responses, with an emphasis on advances in the understanding of the molecular mechanisms that mediate these effects.

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“…A few synthetic approaches have aimed toward the development of ABCA1 / Abca1 inducers. 271 , 336 , 352 , 379 - 382 The cholic acid analog 14b, 336 the thiophene derivative CL2-57, 271 as well as derivatives of N-benzothiazolyl-2-benzenesulfonamide, 379 ginsenoside, 352 and rutaecarpine, 367 all induced ABCA1 / Abca1 mRNA 336 , 352 , 381 and ABCA1 protein 271 , 336 , 379 , 381 content in vitro 271 , 336 , 379 and in vivo , 271 targeting the LXR-α/LXR-β pathway 352 by activation 271 or induction 336 of LXR-α/ LXRA / Lxra and/or LXR-β/ LXRB / Lxrb . In vitro , cholesterol efflux increased 379 , 381 and intracellular cholesterol as well as lipid content were reduced, 336 , 352 while plasma and liver triglycerides levels were reduced in vivo in high fat diet-fed C57BL/6 mice.…”

Section: Part I: Status Quomentioning

confidence: 99%

Strategies to gain novel Alzheimer’s disease diagnostics and therapeutics using modulators of ABCA transporters

Pahnke

Bascuñana

Brackhan

et al. 2021

Free Neuropathology

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Adenosine-triphosphate-(ATP)-binding cassette (ABC) transport proteins are ubiquitously present membrane-bound efflux pumps that distribute endo- and xenobiotics across intra- and intercellular barriers. Discovered over 40 years ago, ABC transporters have been identified as key players in various human diseases, such as multidrug-resistant cancer and atherosclerosis, but also neurodegenerative diseases, such as Alzheimer’s disease (AD). Most prominent and well-studied are ABCB1, ABCC1, and ABCG2, not only due to their contribution to the multidrug resistance (MDR) phenotype in cancer, but also due to their contribution to AD. However, our understanding of other ABC transporters is limited, and most of the 49 human ABC transporters have been largely neglected as potential targets for novel small-molecule drugs. This is especially true for the ABCA subfamily, which contains several members known to play a role in AD initiation and progression. This review provides up-to-date information on the proposed functional background and pathological role of ABCA transporters in AD. We also provide an overview of small-molecules shown to interact with ABCA transporters as well as potential in silico , in vitro , and in vivo methodologies to gain novel templates for the development of innovative ABC transporter-targeting diagnostics and therapeutics.

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Discovery and development of dimeric podocarpic acid leads as potent agonists of liver X receptor with HDL cholesterol raising activity in mice and hamsters

Cited by 23 publications

References 12 publications

Ligands of Therapeutic Utility for the Liver X Receptors

Ligands of Therapeutic Utility for the Liver X Receptors

Biological Roles of Liver X Receptors in Immune Cells

Strategies to gain novel Alzheimer’s disease diagnostics and therapeutics using modulators of ABCA transporters

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