Hydroxyflutamide

Hydroxyflutamide

Clinical data
Other names	2-Hydroxyflutamide; HF; OHF; Flutamide-hydroxide; SCH-16423; Hydroxyniphtholide; Hydroxyniftolide; α,α,α-Trifluoro-2-methyl-4'-nitro-m-lactotoluidide
Drug class	Nonsteroidal antiandrogen
Identifiers
IUPAC name 2-hydroxy-2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]propanamide
CAS Number	52806-53-8
PubChem CID	91649
IUPHAR/BPS	2862
ChemSpider	82752
UNII	31D90UKP5Y
KEGG	C14204
ChEBI	CHEBI:43064
ChEMBL	ChEMBL491
CompTox Dashboard (EPA)	DTXSID8033562
ECHA InfoCard	100.169.708
Chemical and physical data
Formula	C11H11F3N2O4
Molar mass	292.214 g·mol−1
3D model (JSmol)	Interactive image
SMILES CC(C)(C(=O)NC1=CC(=C(C=C1)[N+](=O)[O-])C(F)(F)F)O
InChI InChI=1S/C11H11F3N2O4/c1-10(2,18)9(17)15-6-3-4-8(16(19)20)7(5-6)11(12,13)14/h3-5,18H,1-2H3,(H,15,17) Key:YPQLFJODEKMJEF-UHFFFAOYSA-N

Hydroxyflutamide (developmental code SCH-16423; also known as 2-hydroxyflutamide, HF, and OHF) is a nonsteroidal antiandrogen (NSAA) and the major active metabolite of flutamide, which is considered to be a prodrug of hydroxyflutamide as the active form. ^{[1] [2]} It has been reported to possess an IC₅₀ of 700 nM for the androgen receptor (AR), which is about 4-fold less than that of bicalutamide. ^[3]

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Affinities ^{[a] [4]}

Compound	RBA Tooltip Relative binding affinity [b]
Metribolone	100
Dihydrotestosterone	85
Cyproterone acetate	7.8
Bicalutamide	1.4
Nilutamide	0.9
Hydroxyflutamide	0.57
Flutamide	<0.0057
Notes: At androgen receptors; measured in human prostate tissue. Relative to Metribolone, which is by definition 100%

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Relative affinities of first-generation nonsteroidal antiandrogens for the androgen receptor

Species	IC50 Tooltip Half maximal inhibitory concentration (nM)			RBA Tooltip Relative binding affinity (ratio)
	Bicalutamide	2-Hydroxyflutamide	Nilutamide	Bica / 2-OH-flu	Bica / nilu	Ref
Rat	190	700	ND	4.0	ND	[5]
Rat	~400	~900	~900	2.3	2.3	[6]
Rat	ND	ND	ND	3.3	ND	[7]
Rata	3595	4565	18620	1.3	5.2	[8]
Human	~300	~700	~500	2.5	1.6	[9]
Human	~100	~300	ND	~3.0	ND	[10]
Humana	2490	2345	5300	1.0	2.1	[8]
Footnotes:a = Controversial data. Sources: See template.

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Relative potencies of selected antiandrogens

Antiandrogen	Relative potency
Bicalutamide	4.3
Hydroxyflutamide	3.5
Flutamide	3.3
Cyproterone acetate	1.0
Zanoterone	0.4
Description: Relative potencies of orally administered antiandrogens in antagonizing 0.8 to 1.0 mg/kg s.c. Tooltip subcutaneous injection testosterone propionate-induced ventral prostate weight increase in castrated immature male rats. Higher values mean greater potency. Sources: See template.

References

1. Serra C, Sandor NL, Jang H, Lee D, Toraldo G, Guarneri T, et al. (December 2013). "The effects of testosterone deprivation and supplementation on proteasomal and autophagy activity in the skeletal muscle of the male mouse: differential effects on high-androgen responder and low-androgen responder muscle groups". Endocrinology. 154 (12): 4594–4606. doi:10.1210/en.2013-1004. PMC   3836062 . PMID   24105483.
2. Singh SM, Gauthier S, Labrie F (February 2000). "Androgen receptor antagonists (antiandrogens): structure-activity relationships". Current Medicinal Chemistry. 7 (2): 211–247. doi:10.2174/0929867003375371. PMID   10637363.
3. Furr BJ (June 1995). "Casodex: preclinical studies and controversies". Annals of the New York Academy of Sciences. 761 (3): 79–96. Bibcode:1995NYASA.761...79F. doi:10.1111/j.1749-6632.1995.tb31371.x. PMID   7625752. S2CID   37242269.
4. Ayub M, Levell MJ (August 1989). "The effect of ketoconazole related imidazole drugs and antiandrogens on [3H] R 1881 binding to the prostatic androgen receptor and [3H]5 alpha-dihydrotestosterone and [3H]cortisol binding to plasma proteins". J. Steroid Biochem. 33 (2): 251–5. doi:10.1016/0022-4731(89)90301-4. PMID   2788775.
5. Furr BJ, Valcaccia B, Curry B, Woodburn JR, Chesterson G, Tucker H (June 1987). "ICI 176,334: a novel non-steroidal, peripherally selective antiandrogen". The Journal of Endocrinology. 113 (3): R7 –R9. doi:10.1677/joe.0.113R007. PMID   3625091.
6. Teutsch G, Goubet F, Battmann T, Bonfils A, Bouchoux F, Cerede E, Gofflo D, Gaillard-Kelly M, Philibert D (January 1994). "Non-steroidal antiandrogens: synthesis and biological profile of high-affinity ligands for the androgen receptor". The Journal of Steroid Biochemistry and Molecular Biology. 48 (1): 111–119. doi:10.1016/0960-0760(94)90257-7. PMID   8136296. S2CID   31404295.
7. Winneker RC, Wagner MM, Batzold FH (December 1989). "Studies on the mechanism of action of Win 49596: a steroidal androgen receptor antagonist". Journal of Steroid Biochemistry. 33 (6): 1133–1138. doi:10.1016/0022-4731(89)90420-2. PMID   2615358.
8. Luo S, Martel C, Leblanc G, Candas B, Singh SM, Labrie C, Simard J, Bélanger A, Labrie F (1996). "Relative potencies of Flutamide and Casodex: preclinical studies". Endocrine Related Cancer. 3 (3): 229–241. doi:10.1677/erc.0.0030229. ISSN   1351-0088.
9. Ayub M, Levell MJ (August 1989). "The effect of ketoconazole related imidazole drugs and antiandrogens on [3H] R 1881 binding to the prostatic androgen receptor and [3H]5 alpha-dihydrotestosterone and [3H]cortisol binding to plasma proteins". Journal of Steroid Biochemistry. 33 (2): 251–255. doi:10.1016/0022-4731(89)90301-4. PMID   2788775.
10. Kemppainen JA, Wilson EM (July 1996). "Agonist and antagonist activities of hydroxyflutamide and Casodex relate to androgen receptor stabilization". Urology. 48 (1): 157–163. doi:10.1016/S0090-4295(96)00117-3. PMID   8693644.