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 (HF, OHF) (developmental code name SCH-16423), or 2-hydroxyflutamide, 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]

Affinities[lower-alpha 1][4]
Compound	RBA[lower-alpha 2]
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%

Relative affinities (%) of antiandrogens at steroid-hormone receptors
Antiandrogen	AR	PR	ER	GR	MR
Cyproterone acetate	8–10	60	<0.1	5	1
Chlormadinone acetate	5	175	<0.1	38	1
Megestrol acetate	5	152	<0.1	50	3
Spironolactone	7	0.4^a	<0.1	2^a	182
Trimethyltrienolone	3.6	<1	<1	<1	<1
Inocoterone	0.8	<0.1	<0.1	<0.1	<0.1
Inocoterone acetate	<0.1	<0.1	<0.1	<0.1	<0.1
Flutamide	<0.1	<0.1	<0.1	<0.1	<0.1
Hydroxyflutamide	0.5–0.8	<0.1	<0.1	<0.1	<0.1
Nilutamide	0.5–0.8	<0.1	<0.1	<0.1	<0.1
Bicalutamide	1.8	<0.1	<0.1	<0.1	<0.1
Notes: (1): Reference ligands (100%) were testosterone for the AR, progesterone for the PR, estradiol for the ER, dexamethasone for the GR, and aldosterone for the MR. (2): Tissues were rat prostate (AR), rabbit uterus (PR), mouse uterus (ER), rat thymus (GR), and rat kidney (MR). (3): Incubation times (0°C) were 24 hours (AR, ^a), 2 hours (PR, ER), 4 hours (GR), and 1 hour (MR). (4): Assay methods were different for bicalutamide for receptors besides the AR. Sources: See template.

Relative affinities of first-generation nonsteroidal antiandrogens for the androgen receptor
Species	IC₅₀ (nM)			RBA (ratio)
Species	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]
Rat^a	3595	4565	18620	1.3	5.2	[8]
Human	~300	~700	~500	2.5	1.6	[4]
Human	~100	~300	ND	~3.0	ND	[9]
Human^a	2490	2345	5300	1.0	2.1	[8]
Footnotes: ^a = Controversial data. Sources: See template.

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. testosterone propionate-induced ventral prostate weight increase in castrated immature male rats. Sources: See template.

References

Serra, C; Sandor, NL; Jang, H; Lee, D; Toraldo, G; Guarneri, T; Wong, S; Zhang, A; Guo, W; Jasuja, R; Bhasin, S (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): 4594–606. doi:10.1210/en.2013-1004. PMC 3836062. PMID 24105483.
Singh, Shankar; Gauthier, Sylvain; Labrie, Fernand (2000). "Androgen Receptor Antagonists (Antiandrogens) Structure-Activity Relationships". Current Medicinal Chemistry. 7 (2): 211–247. doi:10.2174/0929867003375371. ISSN 0929-8673. PMID 10637363.
Furr BJ (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.
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.
Furr BJ, Valcaccia B, Curry B, Woodburn JR, Chesterson G, Tucker H (June 1987). "ICI 176,334: a novel non-steroidal, peripherally selective antiandrogen". J. Endocrinol. 113 (3): R7–9. doi:10.1677/joe.0.113R007. PMID 3625091.
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". J. Steroid Biochem. Mol. Biol. 48 (1): 111–9. doi:10.1016/0960-0760(94)90257-7. PMID 8136296.
Winneker RC, Wagner MM, Batzold FH (December 1989). "Studies on the mechanism of action of Win 49596: a steroidal androgen receptor antagonist". J. Steroid Biochem. 33 (6): 1133–8. doi:10.1016/0022-4731(89)90420-2. PMID 2615358.
Luo, S; Martel, C; LeBlanc, G; Candas, B; Singh, S M; Labrie, C; Simard, J; Belanger, 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.
Kemppainen JA, Wilson EM (July 1996). "Agonist and antagonist activities of hydroxyflutamide and Casodex relate to androgen receptor stabilization". Urology. 48 (1): 157–63. doi:10.1016/S0090-4295(96)00117-3. PMID 8693644.

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[4] At androgen receptors; measured in human prostate tissue.

[6] Relative to Metribolone, which is by definition 100%

[1] Serra, C; Sandor, NL; Jang, H; Lee, D; Toraldo, G; Guarneri, T; Wong, S; Zhang, A; Guo, W; Jasuja, R; Bhasin, S (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): 4594–606. doi:10.1210/en.2013-1004. PMC 3836062. PMID 24105483.

[SinghGauthier2000-2] Singh, Shankar; Gauthier, Sylvain; Labrie, Fernand (2000). "Androgen Receptor Antagonists (Antiandrogens) Structure-Activity Relationships". Current Medicinal Chemistry. 7 (2): 211–247. doi:10.2174/0929867003375371. ISSN 0929-8673. PMID 10637363.

[pmid7625752-3] Furr BJ (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.

[pmid2788775-5] 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.

[pmid3625091-7] Furr BJ, Valcaccia B, Curry B, Woodburn JR, Chesterson G, Tucker H (June 1987). "ICI 176,334: a novel non-steroidal, peripherally selective antiandrogen". J. Endocrinol. 113 (3): R7–9. doi:10.1677/joe.0.113R007. PMID 3625091.

[pmid8136296Receptor-8] 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". J. Steroid Biochem. Mol. Biol. 48 (1): 111–9. doi:10.1016/0960-0760(94)90257-7. PMID 8136296.

[pmid2615358-9] Winneker RC, Wagner MM, Batzold FH (December 1989). "Studies on the mechanism of action of Win 49596: a steroidal androgen receptor antagonist". J. Steroid Biochem. 33 (6): 1133–8. doi:10.1016/0022-4731(89)90420-2. PMID 2615358.

[LuoMartel1996-10] Luo, S; Martel, C; LeBlanc, G; Candas, B; Singh, S M; Labrie, C; Simard, J; Belanger, 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.

[pmid8693644-11] Kemppainen JA, Wilson EM (July 1996). "Agonist and antagonist activities of hydroxyflutamide and Casodex relate to androgen receptor stabilization". Urology. 48 (1): 157–63. doi:10.1016/S0090-4295(96)00117-3. PMID 8693644.