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Differential Effects of Lipid-lowering Drugs in Modulating Morphology of Cholesterol Particles
Published on: November 10, 2017
Steroidal glycoside cholesterol absorption inhibitors
M P DeNinno1, P A McCarthy, K C Duplantier
1Central Research Division, Pfizer Inc. Groton, Connecticut 06340, USA. deninm@pfizer.com
Journal of Medicinal Chemistry
|August 1, 1997
Summary
Researchers investigated steroidal glycosides for cholesterol absorption inhibition. Optimized derivatives, like compound 51, showed significantly enhanced potency, offering potential new therapeutic strategies.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Biochemistry
Background:
- Steroidal glycosides are being explored as potential cholesterol absorption inhibitors.
- The exact mechanism of action for these compounds remains unknown.
Purpose of the Study:
- To discover and optimize steroidal glycosides with improved cholesterol absorption inhibitory activity.
- To identify key structural modifications that enhance potency.
Main Methods:
- Synthesis and evaluation of steroidal glycoside analogs in an acute hamster cholesterol absorption assay.
- Structure-activity relationship (SAR) studies focusing on modifications of the steroid and sugar moieties.
Main Results:
- Tigogenin cellobioside (tiqueside) demonstrated weak inhibition (ED50 = 60 mg/kg).
- 11-ketotigogenin cellobioside (pamaqueside) showed increased potency (ED50 = 2 mg/kg).
- Modification of hydroxyl groups on the cellobiose led to highly potent analogs, including compound 51 (ED50 = 0.025 mg/kg) and compound 64 (ED50 = 0.07 mg/kg).
Conclusions:
- Structural modifications, particularly on the hydroxyl groups of the glycosidic moiety, significantly enhance the cholesterol absorption inhibitory activity of steroidal glycosides.
- The developed compounds represent potent leads for further investigation as cholesterol-lowering agents.
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