Colestolone Explained

Colestolone, also known as 5α-cholest-8(14)-en-3β-ol-15-one, is a potent inhibitor of sterol biosynthesis which is described as a hypocholesterolemic (lipid-lowering) agent.^{[1] [2] [3] [4] [5]} It was first reported in 1977 and was studied until at least 1988, but was never introduced for medical use.

Colestolone has been found to significantly reduce serum levels of cholesterol both in animals and in humans. It inhibits multiple relatively early-stage steps in cholesterol biosynthesis such as HMG-CoA reductase^[6] and does not appear to affect any late-stage steps (after squalene, specifically). Unlike late-stage cholesterol biosynthesis inhibitors like triparanol and azacosterol, no accumulation of sterols has been observed in animals treated with colestolone, suggesting that it does not share the toxicity of late-stage cholesterol biosynthesis inhibitors.

In addition to its potent inhibition of cholesterol biosynthesis, it is notable that colestolone also happens to serve as a precursor of cholesterol, and is efficiently converted into it in rat liver homogenates and upon oral administration to rats.

Notes and References

1. Book: J. Elks. The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. 14 November 2014. Springer. 978-1-4757-2085-3. 646–.
2. Book: Daniel Lednicer. Strategies for Organic Drug Synthesis and Design. 4 March 2009. John Wiley & Sons. 978-0-470-39959-0. 186–.
3. Web site: 9α-hydroxy-3-oxo-4,24(25)-stigmastadien-26-oic acid derivatives, a process for preparing same and pharmaceutical compositions containing same.
4. Schroepfer GJ, Chu AJ, Needleman DH, Izumi A, Nguyen PT, Wang KS, Little JM, Sherrill BC, Kisic A . Inhibitors of sterol synthesis. Metabolism of 5 alpha-cholest-8(14)-en-3 beta-ol-15-one after intravenous administration to bile duct-cannulated rats . J. Biol. Chem. . 263 . 9 . 4110–23 . 1988 . 10.1016/S0021-9258(18)68897-0 . 3346239 . free .
5. Schroepfer GJ, Parish EJ, Kisic A, Jackson EM, Farley CM, Mott GE . 5 alpha-Cholest-8(14)-en-3 beta-ol-15-one, a potent inhibitor of sterol biosynthesis, lowers serum cholesterol and alters distributions of cholesterol in lipoproteins in baboons . Proc. Natl. Acad. Sci. U.S.A. . 79 . 9 . 3042–6 . 1982 . 6953447 . 346345 . 10.1073/pnas.79.9.3042. 1982PNAS...79.3042S . free .
6. Book: Pharmaceutical R&D costs, risks, and rewards.. 1993. DIANE Publishing. 978-1-4289-2103-0. 25–.