Halotestin, Ultandren, Androfluorene, Android-F, Ora-Testryl, Stenox
The Upjohn team developed an interest in the anabolic potential of steroids after observation of extensive clinical trials of “deponortestonate” (their own injectable nandrolone product) and proceeded to develop and test a number of novel compounds.
One of Upjohn’s most significant discoveries was made in the 1950s, when they discovered a microbiological fermentation technique for introducing an oxygen atom at the 11th carbon atom of a steroid.  Not only did this enable large-scale production of corticosteroids like cortisone, but it also paved the way for the creation of halotestin.
The results of experiments on rats given some of the 11-oxygenated steroids prepared by Upjohn can be seen below: 
As you can see from the figures, all of the 11-oxygenated steroids were found to be significantly stronger than their non-oxygenated counterparts.
9α-halogenated corticosteroid derivatives were first described by Fried and Sabo in 1953  and were found to have enhanced glucocorticoid and anti-inflammatory activity. With this in mind, Lyster et al at Upjohn synthesized and tested a variety of 9α-halogenated 11β-hydroxylated testosterone derivatives. 
They found that while a 9-chloro group abolished activity, the 9α-fluoro substituted steroid produced a remarkable increase in the oral anabolic and androgenic activity in rats. 
“11β-Hydroxy-methyltestosterone is 0.9 times as potent as methyltestosterone as an androgen and 3 times as potent as a myotrophic agent. 9-Fluoro-11β-hydroxy-methyltestosterone is 9.5 times as potent as methyltestosterone as an androgen and 20 times as potent as a myotrophic agent.” 
The compound 9α-fluoro 11β-hydroxy 17α-methyltestosterone was subsequently trivialised to fluoxymesterone.
- 2000 : 950 vs. 17α-methyl-testosterone by oral administration (Lyster et al, 1956). 
The Upjohn researchers found fluoxymesterone had an A:A ratio of 2000:950 vs. methyl testosterone by oral administration. 
- 1745 : 757-118 vs. 17α-methyl-testosterone by oral administration (Kincl and Dorfman, 1963). 
The Upjohn figures were later supported in 1963 by Syntex researchers Kincl and Dorfman who confirmed LA, SV, and VP figures of 1745%, 757%, and 118% respectively. 
- 380 : 140 vs. 17α-methyl-testosterone by oral administration (nitrogen retention:ventral prostate) (Beyler et al, 1963). 
When revisited in 1963 by Beyler et al, the anabolic (as measured by nitrogen retention) to androgenic (measured by ventral prostate) ratios of both bolasterone and fluoxymesterone were found to be “considerably less than that reported for certain… heterocyclic steroids of current clinical interest.“,  of course their position may have been coloured somewhat by their commercial position; as researchers at Sterling-Winthrop they were responsible for creating the steroid stanozolol – more commonly known as Winstrol. 
Structurally classified as a testosterone derivative, fluoxymesterone possesses a 17α-methyl group common to many oral AAS. This structural modification permits high oral bioavailability through the prevention of 17β-hydroxyl oxidation.
What makes fluoxymesterone particularly distinct from other available anabolic steroids is the substitution of a fluorine atom in the 9α position. While it’s an anomaly in the world of androgens, this is relatively common among synthetic glucocorticoids; it graces the likes of dexamethasone, betamethasone, fludrocortisone, and triamcinolone.
In fact there are some compounds that are substituted at 9α with other halogens. For example, beclometasone has a 9α-chloro function. Schering even tested some 9α,11β-dihalogenated compounds, with limited success, although the dichlorinated dianabol derivative showed some promise with an anabolic:androgenic ratio of 300:60 vs MT by oral admin. 
It is not entirely clear why the 9-alpha-fluoro moiety imparts such high anabolic/androgenic activity to fluoxymesterone given orally, but the fluorine atom can potentially change the pharmacokinetics and pharmacodynamics of a drug in several ways:
“(1) Fluorine, because of its small steric size, resembles bioactive hydrogen with respect to steric environment in association with protein receptor regions;
(2) Fluorine, the most electronegative element, alters electronic effects;
(3) Fluorine, which when bonded to carbon has a carbon-fluorine bond energy of 107 kcal/mole, increases the oxidative, thermal, and metabolic stability; and
(4) Perhaps most importantly, carbon-fluorine bonds substantially increase lipid solubility and thereby enhance the rates of bioabsorption and biotransport.” 
In accordance with the first property mentioned above, the fluorine atom has a very similar van der Waals radius to the hydrogen atom it replaces.  Standard radii for hydrogen lie around 1.1Å-1.2Å and for fluorine around 1.35Å-1.47Å. 
In addition to its unusual 9α-fluoro group, fluoxymesterone also has an 11β-hydroxyl group which is characteristic of many active corticosteroids. A recent study has found that due to this 11β-hydroxyl fluoxymesterone interferes with corticosteroid metabolism.
Cortisol is converted to inactive cortisone by the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). Since the mineralocorticoid receptor (MR) can be activated by both mineralocorticoids and glucocorticoids, this enzyme is expressed in mineralocorticoid-sensitive tissues to prevent activation of the MR by cortisol. Fluoxymesterone was found to be a potent competitive inhibitor of human 11β-HSD2.  This inhibition could cause cortisol-induced MR activation, leading to retention of sodium and excretion of potassium, causing fluid retention and hypertension.
Following the successful clinical use of fluoxymesterone, some 16α-methylated variations were synthesized and tested by Merck, though they were found to be disappointingly inactive by comparison. 
Despite the 9α-fluoro and 11β-hydroxyl group modifications, fluoxymesterone undergoes both 5α-reduction and 5β-reduction in humans.  3-keto reduced metabolites have also been detected in man. 
Although 9a-fluoro-testosterone aromatizes at around half the rate of testosterone, the 11β-hydroxyl group of fluoxymesterone will prevent aromatization. 
“The presence of axial substituents at carbon 11 interferes with ring A aromatization.” 
As with all 17α-alkyl-17β-hydroxy steroids, 17-keto metabolites of fluoxymesterone are impossible. 17-epimerization of fluoxymesterone has been reported and is a common (though minor) metabolic pathway among 17α-methyl-17β-hydroxy steroids. 
The presence of several hydroxylated, dihydroxylated, 11,12 and 13,14 unsaturated, and 11-keto metabolites have also been identified (post-administration) in humans, according to a recent study. It is also worth noting that fluoxymesterone is metabolized to its corresponding 11-keto analogue “11-oxofluoxymesterone” by human 11β-HSD2 (though not extensively), as demonstrated by a contemporary in vitro experiment.
“Biological data showed that fluoxymesterone is a substrate of 11β-HSD2, but with a lower conversion rate than cortisol.” 
 Steroids 57, Issue 12, 593-616
 Hormonal Steroids 2, Academic Press 1965, 59-67
 J. Am. Chem. Soc., 1953, 75 (9), pp 2273–2274
 Endocrinology 58, 781 (1956)
 Endocrinology. 1963 Jan 2;72(2):259–66.
 J Endocrinol 1963 28 87-92
 Endocrinology 1961 vol. 68 no. 6 987-995
 Proc. 1st Int.Congr. Hormonal Steroids, 2, pp119-132, Academic Press, New York (1965)
 J Am Chem Soc 82, 4611 (1960)
 J. Chem. Educ., 1979, 56 (4), p 228
 Androgens and Anabolic Agents. 1969. Academic Press. p. 63
 J. Phys. Chem., 1964 Mar;68 (3):441-551
 J. Phys. Chem., 1996 May;100 (18), pp 7384–7391
 Toxicological Sciences. 2012 Apr;126(2):353-61.
 J Org Chem 27, 682 (1962)
 J. Am. Chem. Soc., 1956, 78 (2), pp 500–501
 Steroids. 2012 Jul;77(8-9):871-877.
 J. Steroid Biochem. 1990 Aug;36(6):659-666.
 Endocrinology. 1962 Dec;71:920–925.
 Endocrinology. 1980 Feb;106(2):440-3.
 Steroids. 1992 Nov;57(11):537-50.
© Total Flex Blog 2012