Description
Tibolone is a synthetic steroid with weak progestational and estrogenic properties,
reportedly useful in controlling symptoms resulting from natural or surgical menopause.
It has thus far shown no significant antithrombotic effect in post-menopausal patients.
Chemical Properties
White Solid
Originator
Akzo (Organon) (The Netherklands)
Uses
A synthetic steroid with weak estrogenic, androgenic and progestogenic activity. A pharamceutical used in the treatment of menopausal syndrome
Definition
ChEBI: Estran-3-one with a double bond between positions 5 and 10, and bearing both an ethynyl group and a hydroxy group at position 17 (R-configuration). A synthetic steroid hormone drug which acts as an agonist at all five type I steroid hormon
receptors, it is used in the prevention of postmenopausal osteoporosis and for treatment of endometriosis.
Pharmacokinetics
Raloxifene is rapidly absorbed following oral administration, with an estimated 60% absorption, but it has a
very low bioavailability (2%), associated with extensive phase II metabolism. The metabolites are excreted via
the bile, with potential enterohepatic recycling that could account for the interaction with cholestyramine.
Supportive of the enterohepatic recycling is the half-life of 28 hours. Metabolism of raloxifene occurs to a great
extent in the intestine and consists of glucuronide conjugation catalyzed by uridine diphosphate
glucuronosyltransferase (UGT).
Clinical Use
Tibolone is a synthetic steroid that has been shown to increase bone mineral density similar to
alendronate. The U.S. FDA approval is pending; overseas, this agent is used for the treatment of
menopausal symptoms as well as the prevention of osteoporosis. It is considered to be a viable
alternative to conjugated equine estrogen plus micronized progesterone.
Side effects
The most common reason for
patient withdrawal from clinical trials was vaginal bleeding (also a common side effect when estrogen
therapy is used).
Synthesis
The 1,4-diene intermediate was obtained by Birch reduction (lithium metal/liquid ammonia); subsequently, it was hydrolyzed under acidic conditions and protected by ketalization of the 3-keto group (e.g., to prepare a 3,3-dimethoxy derivative); then, the 17-hydroxyl group was oxidized to a ketone and a 17α-ethynyl group was introduced by nucleophilic addition of acetylene; finally, the 3-protecting group was removed by hydrolysis under mild acidic conditions to obtain Tibolone.
References
[1] Deng, X. F., Feng, C. G., Zhang, T. B., & Zheng, C. G. (2006). Studies on synthesis of tibolone. Journal of Chinese Pharmaceutical Sciences, 41(16), 1274-1275+1280.
