Chemical compound
Fluasterone
Other names 3β-Dehydroxy-16α-fluoro-DHEA; Fl-DHEA; DHEF; DHEA 8354; DHEA analogue 8354; HE-2500; 16α-Fluoroandrost-5-en-17-one
(8 R,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 )
Formula C 19 H 27 F O
Molar mass 290.422 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.
[1]
[2] 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.
[3]
The
mechanism of action of DHEA and fluasterone is unknown.
[4]
[5]
[6] However, similarly to DHEA but more strongly, fluasterone is a
potent
uncompetitive inhibitor of
G6PDH Tooltip glucose-6-phosphate dehydrogenase (Ki = 0.5 μM versus 17 μM for DHEA).
[4] 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).
[4]
[6]
[7]
[8]
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 .
[6]
[9]
[4] 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 .
[10] In addition, unlike DHEA, fluasterone has reduced or no effects as a
peroxisome proliferator (i.e., lacks activity at the
PPARα Tooltip peroxisome proliferator-activated receptor alpha ), and hence does not pose a risk of
liver toxicities such as
hepatomegaly or
hepatocellular carcinoma .
[4] It is for these reasons that fluasterone was developed and was considered to be advantageous to DHEA.
[4]
[6]
Due to extensive
first-pass
hepatic and/or
gastrointestinal metabolism, very high doses of DHEA and fluasterone are necessary for effectiveness.
[4] 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.
[4] 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.
[11]
References
^
"Fluasterone" . AdisInsight . S pringer Nature Switzerland AG.
^ 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 .
^ 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 .
^
a
b
c
d
e
f
g
h 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 .
^ 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 .
^
a
b
c
d 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 .
^ 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 .
^ 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 .
^ 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 .
^ 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 .
^ 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 .
External links