Fluasterone

Fluasterone
Clinical data
Other names3β-Dehydroxy-16α-fluoro-DHEA; Fl-DHEA; DHEF; DHEA 8354; DHEA analogue 8354; HE-2500; 16α-Fluoroandrost-5-en-17-one
Identifiers
  • (8R,9S,10R,13S,14S,16R)-16-Fluoro-10,13-dimethyl-1,2,3,4,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-one
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC19H27FO
Molar mass290.422 g·mol−1
3D model (JSmol)
  • C[C@]12CCCCC1=CC[C@@H]3[C@@H]2CC[C@]4([C@H]3C[C@H](C4=O)F)C
  • InChI=1S/C19H27FO/c1-18-9-4-3-5-12(18)6-7-13-14(18)8-10-19(2)15(13)11-16(20)17(19)21/h6,13-16H,3-5,7-11H2,1-2H3/t13-,14+,15+,16-,18+,19+/m1/s1
  • Key:VHZXNQKVFDBFIK-NBBHSKLNSA-N

Fluasterone, also known as 3β-dehydroxy-16α-fluoro-DHEA or 16α-fluoroandrost-5-en-17-one, is a fluorinated synthetic analogue of dehydroepiandrosterone (DHEA) which was under investigation by Aeson Therapeutics for a variety of therapeutic indications including cancer, cardiovascular diseases, diabetes, obesity, and traumatic brain injury among others but was ultimately never marketed. It is a modification of DHEA in which the C3β hydroxyl has been removed and a hydrogen atom has been substituted with a fluorine atom at the C16α position. Fluasterone reached phase II clinical trials prior to the discontinuation of its development.

The mechanism of action of DHEA and fluasterone is unknown. However, similarly to DHEA but more strongly, fluasterone is a potent uncompetitive inhibitor of G6PDHTooltip glucose-6-phosphate dehydrogenase (Ki = 0.5 μM versus 17 μM for DHEA). The drug retains the antiinflammatory, antihyperplastic, chemopreventative, antihyperlipidemic, antidiabetic, and antiobesic, as well as certain immunomodulating activities of DHEA, much but not all of which it is thought may possibly be mediated via G6PDH inhibition (with some experimental evidence to support this notion available).

Conversely, unlike DHEA, fluasterone has minimal or no androgenic or estrogenic activity, and due to the presence of the fluorine atom at the C16α position, its metabolism at the C17α position is sterically hindered and thus it cannot be metabolized into androgens like testosterone or estrogens like estradiol. Also in contrast to DHEA, fluasterone does not produce sedation or seizures in animals and hence is not thought to interact with the GABAA receptor. In addition, unlike DHEA, fluasterone has reduced or no effects as a peroxisome proliferator (i.e., lacks activity at the PPARαTooltip peroxisome proliferator-activated receptor alpha), and hence does not pose a risk of liver toxicities such as hepatomegaly or hepatocellular carcinoma. It is for these reasons that fluasterone was developed and was considered to be advantageous to DHEA.

Due to extensive first-pass hepatic and/or gastrointestinal metabolism, very high doses of DHEA and fluasterone are necessary for effectiveness. In animals, the efficacy of fluasterone is increased 40-fold when administered parenterally, and for this reason, a non-oral formulation of fluasterone was selected for clinical development. However, the development of fluasterone was nonetheless stopped reportedly due to its low potency and low oral bioavailability, which are said to have rendered it unsuitable for clinical use.

References

  1. ↑ "Fluasterone". AdisInsight. S pringer Nature Switzerland AG.
  2. ↑ Gravanis AG, Mellon SH (24 June 2011). "Neuroprotective and Neurogenic Properties of Dehydroepiandrosterone and its Synthetic Analogs". Hormones in Neurodegeneration, Neuroprotection, and Neurogenesis. John Wiley & Sons. pp. 170–. ISBN 978-3-527-63397-5.
  3. ↑ Bégué JP, Bonnet-Delpon D (6 June 2008). "Biological Impactes of Fluorination: Pharmaceuticals Based on Natural Products". In Tressaud A, Haufe G (eds.). Fluorine and Health: Molecular Imaging, Biomedical Materials and Pharmaceuticals. Elsevier. pp. 603–. ISBN 978-0-08-055811-0.
  4. 1 2 3 4 5 6 7 8 Schwartz AG, Pashko LL (April 2004). "Dehydroepiandrosterone, glucose-6-phosphate dehydrogenase, and longevity". Ageing Research Reviews. 3 (2): 171–187. doi:10.1016/j.arr.2003.05.001. PMID 15177053. S2CID 11871872.
  5. ↑ Schwartz AG, Pashko LL (2001). "Potential therapeutic use of dehydroepiandrosterone and structural analogs". Diabetes Technology & Therapeutics. 3 (2): 221–224. doi:10.1089/152091501300209589. PMID 11478328.
  6. 1 2 3 4 Ciolino HP, MacDonald CJ, Yeh GC (July 2002). "Inhibition of carcinogen-activating enzymes by 16alpha-fluoro-5-androsten-17-one". Cancer Research. 62 (13): 3685–3690. PMID 12097275.
  7. ↑ McCormick DL, Johnson WD, Kozub NM, Rao KV, Lubet RA, Steele VE, Bosland MC (February 2007). "Chemoprevention of rat prostate carcinogenesis by dietary 16alpha-fluoro-5-androsten-17-one (fluasterone), a minimally androgenic analog of dehydroepiandrosterone". Carcinogenesis. 28 (2): 398–403. doi:10.1093/carcin/bgl141. PMID 16952912.
  8. ↑ Auci D, Kaler L, Subramanian S, Huang Y, Frincke J, Reading C, Offner H (September 2007). "A new orally bioavailable synthetic androstene inhibits collagen-induced arthritis in the mouse: androstene hormones as regulators of regulatory T cells". Annals of the New York Academy of Sciences. 1110 (1): 630–640. Bibcode:2007NYASA1110..630A. doi:10.1196/annals.1423.066. PMID 17911478. S2CID 32258529.
  9. ↑ Brown AP, Kirchner DL, Morrissey RL, Das SR, Fitzgerald RL, Crowell JA, Levine BS (2003). "Endocrine effects of dehydroepiandrosterone and its fluorinated analog, fluasterone, in rats". Drug Development Research. 58 (2): 169–178. doi:10.1002/ddr.10156. ISSN 0272-4391. S2CID 98206458.
  10. ↑ Malik AS, Narayan RK, Wendling WW, Cole RW, Pashko LL, Schwartz AG, Strauss KI (May 2003). "A novel dehydroepiandrosterone analog improves functional recovery in a rat traumatic brain injury model". Journal of Neurotrauma. 20 (5): 463–476. doi:10.1089/089771503765355531. PMC 1456324. PMID 12803978.
  11. ↑ Auci DL, Ahlem CN, Reading CL, Frincke JM (22 July 2011). "DHEA and Its Metabolites and Analogs: A Role in Immune Modulation and Arthritis TreatmentWatson RS". DHEA in Human Health and Aging. CRC Press. pp. 212–. ISBN 978-1-4398-3884-6.