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]

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Affinities^[a]^[4]
Compound	RBATooltip 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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t
e
Relative affinities of first-generation nonsteroidal antiandrogens for the androgen receptor
Species	IC₅₀Tooltip Half maximal inhibitory concentration (nM)			RBATooltip Relative binding affinity (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	^[9]
Human	~100	~300	ND	~3.0	ND	^[10]
Human^a	2490	2345	5300	1.0	2.1	^[8]
Footnotes: ^a = Controversial data. Sources: See template.

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t
e
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

^ 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.
^ 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.
^ 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.
^ 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". The Journal of Endocrinology. 113 (3): R7–R9. 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". The Journal of Steroid Biochemistry and Molecular Biology. 48 (1): 111–119. doi:10.1016/0960-0760(94)90257-7. PMID 8136296. S2CID 31404295.
^ 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.
^ ^a ^b 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.
^ 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.
^ 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.

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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, 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.

[SinghGauthier2000-2] 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.

[pmid7625752-3] 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.

[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". The Journal of Endocrinology. 113 (3): R7–R9. 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". The Journal of Steroid Biochemistry and Molecular Biology. 48 (1): 111–119. doi:10.1016/0960-0760(94)90257-7. PMID 8136296. S2CID 31404295.

[pmid2615358-9] 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.

[LuoMartel1996-10] 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.

[Ayub_1989-11] 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.

[pmid8693644-12] 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.

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Hydroxyflutamide

References

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