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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
- Source :
- Bioorganic & Medicinal Chemistry Letters. 15:2824-2828
- Publication Year :
- 2005
- Publisher :
- Elsevier BV, 2005.
-
Abstract
- Liver X receptors are nuclear receptors that regulate metabolism of cholesterol. They are activated by oxysterols resulting in increased transcription of the ABCA1 gene, promoting cholesterol efflux and HDL formation. We have identified podocarpic acid anhydride as a 1 nM agonist of LXRα and β receptors. Functionally this agonist was over 8–10-fold better activator of LXR receptors compared to one of the natural ligands, 22-(R)-hydroxy cholesterol, in HEK-293 cells. An imide analog increased the level of HDL by 26%, decreased LDL by 10.6%, and increased triglyceride by 51% in hamsters. Discovery, synthesis, SAR and details of the activities of dimers have been described.
- Subjects :
- Male
Agonist
medicine.medical_specialty
medicine.drug_class
Clinical Biochemistry
Receptors, Cytoplasmic and Nuclear
Pharmaceutical Science
Biochemistry
Cell Line
Rats, Sprague-Dawley
Mice
Structure-Activity Relationship
chemistry.chemical_compound
Cricetinae
Internal medicine
Drug Discovery
medicine
Animals
Humans
Liver X receptor
Receptor
Molecular Biology
Biotransformation
Triglyceride
Activator (genetics)
Cholesterol
Cholesterol, HDL
Organic Chemistry
Metabolism
Phenanthrenes
Rats
Endocrinology
chemistry
Nuclear receptor
Area Under Curve
Abietanes
Molecular Medicine
lipids (amino acids, peptides, and proteins)
Dimerization
Subjects
Details
- ISSN :
- 0960894X
- Volume :
- 15
- Database :
- OpenAIRE
- Journal :
- Bioorganic & Medicinal Chemistry Letters
- Accession number :
- edsair.doi.dedup.....e91291554a85a4cdd26920f44ff0310f