| Identification | More | [Name]
Bicalutamide | [CAS]
90357-06-5 | [Synonyms]
BICALUTAMIDE
CASODEX
ICI-176334
N-[(4-CYANO-3-TRIFLUOROMETHYL)PHENYL]-3-[(4-FLUOROPHENYL)SULFONYL]-2-HYDROXY-2-METHYLPROPANAMIDE
N-[4-CYANO-3-(TRIFLUOROMETHYL)PHENYL]-3-[(4-FLUOROPHENYL)SULFONYL]-2-HYDROXY-2-METHYLPROPIONANILIDE
(+-)--2-hydroxy-2-methyl
propanamide,n-(4-cyano-3-(trifluoromethyl)phenyl)-3-((4-fluorophenyl)sulfonyl)
Bicalutamide (Subject to patent free)
Bicalutamide&Int.
ICI-176334, Casodex, N-[4-Cyano-3-trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide
4-cyano-3-trifluoromethyl-N-(3-p-fluorophenylsulfonyl-2-hydroxy-2-methylpropionyl)aniline (bicalutamide)
4''-CYANO-3-[(4-FLUROPHENYL)SULFONYL]-2-HYDROXY-3-METHYL-3''-(TRIFUROMETHYL)-PROPIONANILIDE
(+-)-4'-Cyano-α,α,α-trifluoro-3-[(p-fluorophenyl)sulfonyl]-2-methyl-m-lactotoluidide
Cosudex
Propanamide, N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methyl-
Propanamide, N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methyl-, (+-)-
Bicaiutamide | [EINECS(EC#)]
200-001-8 | [Molecular Formula]
C18H14F4N2O4S | [MDL Number]
MFCD00869971 | [Molecular Weight]
430.37 | [MOL File]
90357-06-5.mol |
| Chemical Properties | Back Directory | [Appearance]
Off-White Crystalline Solid | [Melting point ]
191-193°C | [Boiling point ]
650.3±55.0 °C(Predicted) | [density ]
1.52±0.1 g/cm3(Predicted) | [storage temp. ]
2-8°C | [solubility ]
DMSO: >5mg/mL | [form ]
powder | [pka]
11.49±0.29(Predicted) | [color ]
White to Off-White | [Usage]
Non-steroidal peripherally active antiandrogen. Used as an antiandrogen, antineoplastic (hormonal) | [λmax]
270nm(CH3CN)(lit.) | [Merck ]
14,1200 | [InChI]
InChI=1S/C18H14F4N2O4S/c1-17(26,10-29(27,28)14-6-3-12(19)4-7-14)16(25)24-13-5-2-11(9-23)15(8-13)18(20,21)22/h2-8,26H,10H2,1H3,(H,24,25) | [InChIKey]
LKJPYSCBVHEWIU-UHFFFAOYSA-N | [History]
Bicalutamide was discovered in the 1980s by Tucker et al. at Imperial Chemical Industries (now AstraZeneca). Based on previous works on flutamide, key structural features required for a strong anti-androgenic activity include the presence of an electron-poor aromatic ring, attached to an amide moiety. Electron-withdrawing groups at the para and the meta position of the anilide ring are beneficial for the anti-androgenic activity as compared to monosubstituted derivatives.As far as the meta position is concerned, a chloro or trifluoromethyl substituent is the best choice. Nitro and cyano groups are the best substituents at the para position. Replacement of themethyl group at the tertiary carbinol center by a trifluoromethyl group resulted in compounds with agonistic activity. In contrast to flutamide, the amide moiety of bicalutamide was extended by a sulfur linker with a second aromatic portion. The sulfanyl, sulfinyl, and sulfonyl analogues showed the same activity.The sulfanyl group was found to be oxidized to the active metabolite sulfonyl, thus indicating the sulfonyl derivative as the biologically active entity. An unsubstituted phenylsulfonyl moiety at the eastern part, or corresponding derivatives with small substituents such as fluoro at the para position, seemed to be the best in terms of anti-androgenic activity. | [SMILES]
C(NC1=CC=C(C#N)C(C(F)(F)F)=C1)(=O)C(O)(C)CS(C1=CC=C(F)C=C1)(=O)=O | [CAS DataBase Reference]
90357-06-5(CAS DataBase Reference) |
| Safety Data | Back Directory | [Hazard Codes ]
Xi | [Risk Statements ]
R36/37/38:Irritating to eyes, respiratory system and skin . | [Safety Statements ]
S26:In case of contact with eyes, rinse immediately with plenty of water and seek medical advice .
S36:Wear suitable protective clothing . | [RIDADR ]
3077 | [WGK Germany ]
3 | [RTECS ]
TX1413500 | [HazardClass ]
9 | [PackingGroup ]
III | [HS Code ]
29309099 | [Hazardous Substances Data]
90357-06-5(Hazardous Substances Data) |
| Hazard Information | Back Directory | [Description]
Bicalutamide was launched in the United Kingdom, its first worldwide market, for
the treatment of advanced prostate cancer in combination with an LHRH analog or
surgical castration. A non-steroidal, peripherally selective antiandrogen, bicalutamide
inhibits the action of dihydrotestosterone and testosterone at target sites by
competitive binding to the cytosolic androgen receptor. It was reportedly well tolerated
with no significant cardiovascular and metabolic side effects due to the benefit of
lacking any steroid activity. The efficacy of bicalutamide as a monotherapy has been
demonstrated clinically. Promising response rates were also reported in treating
colorectal, breast, pancreas and non-small cell lung cancers. | [Chemical Properties]
Off-White Crystalline Solid | [Originator]
Zeneca (United Kingdom) | [Uses]
Bicalutamide (CDX) has been used as an androgen receptor (AR) antagonist in prostate, bladder cancer cell lines and human fetal skeletal muscle cells. It has also been used as a supplement in RPMI 1640 for culturing androgen-independent LNCaP (LNCaP-AI) cell line. | [Uses]
These Secondary Standards are qualified as Certified Reference Materials. These are suitable for use in several analytical applications including but not limited to pharma release testing, pharma method development for qualitative and quantitative analyses, food and beverage quality control testing, and other calibration requirements. | [Uses]
adrenocortical suppressant, antineoplastic, steroid biosynthesis inhibitor | [Uses]
Non-steroidal peripherally active antiandrogen. Used as an antiandrogen, antineoplastic (hormonal) | [Definition]
ChEBI: A sulfone that is an oral non-steroidal antiandrogen used in the treatment of prostate cancer and hirsutism. | [Indications]
Bicalutamide was the third nonsteroidal anti-androgen that was used for the treatment of prostate cancer. Flutamide, although effective in the treatment of prostate cancer, is a pure antagonist that also affects the hypothalamus pituitary axis, thus preventing the negative feedback mechanism of androgen. Consequently, the production of LH is increased, which subsequently stimulates the synthesis of testosterone, counteracting the effectiveness of the anti-androgen. Furthermore, the half-life of the active metabolite of flutamide, hydroxyflutamide, is fairly short, and a dosing scheme of 250 mg three times daily is therefore required. The main adverse effects reported for flutamide are gynecomastia, diarrhea, and reversible liver abnormalities. Nilutamide has a longer half-life than flutamide and therefore can be administered once daily. Adverse events reported include problems with light/dark adaptation and interstitial pneumonitis. The goal that ultimately led to the discovery of bicalutamide was the identification of a novel peripherally selective anti-androgen with longer half-life than flutamide and with better tolerability as compared to both, flutamide and nilutamide. | [Manufacturing Process]
[(4S)-4-Methyl-5-oxo-2-(tribromomethyl)-1,3-dioxolan-4-yl]acetic acid.
Bromal (25.0 g; 89.1 mmol) and (S)-citramalic acid (11.0 g; 74.2 mmol) were
cooled to 0°C under inert atmosphere. Sulfuric acid/acetic acid (1/1; 25 ml)
was added dropwise with stirring. After 2 h the contents were a yellow
solution with a white precipitate. The ice bath was removed and the reaction
mixture was stirred overnight at room temperature. The reaction mixture was
diluted with ice and extracted 4 times with ethyl acetate. The organic layer
was back extracted with water and then was dried with MgSO4. After filtration,
the filtrate was concentrated to an oil. The product was obtained as a white
solid after crystallization from toluene/hexanes. Yield: 23.2 g (77%); mp
151°C (sublime).
(5R)-5-(Bromomethyl)-5-methyl-2-(tribromo-methyl)-l,3-dioxolan-4-one.
The above obtained [(4S)-4-Methyl-5-oxo-2-(tribromomethyl)-1,3-dioxolan-4-
yl]acetic acid (102.5 mg; 0.250 mmol) and 2-mercaptopyridine- N-oxide (34.4
mg; 0.280 mmol) were suspended in CBrCl3 (1.5ml). The reaction mixture
was heated to reflux and a solution of dicyclohexyl carbodiimide (DCC) (103
mg; 0.500 mmol) in CBrCl3 (1.0 ml) was added slowly over the course of 30
min. The reaction mixture was stirred for an additional hour. The product was
purified by silica gel chromatography (CH2Cl2/hexanes (1:2)) and was
obtained as white needles from the same solvents. Yield: 72 mg (65%); mp
110-113°C.
(2R)-3-[(4-Fluorophenyl)thio]-2-hydroxy-2-methyl-propanoic acid.
The above prepared protected hydroxyacid (184 mg; 0.413 mmol) was
dissolved in 4 ml of a 1:1 mixture of isopropanol:1 M NaOH. After 3 h, the
reaction mixture was a solution and no starting material was detectable by
TLC. 4-Fluorobenzenethiol (70 ml; 0.65 mmol) was then added and the
reaction mixture was stirred overnight. The reaction mixture was then adjusted to pH 8 with HCl and was extracted twice with CH2Cl2. The aqueous
layer was then adjusted to pH 1 and was extracted with CH2Cl2. This organic
layer was concentrated to an oil, which crystallized on standing. The
hydroxyacid was either used in the next reaction without further purification
or was recrystallized from chloroform/petroleum ether. Yield 76 mg (80%).
(2R)-N-[4-Cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenul)thio]-2-
hydroxy-2-methylpropanamide was prepared from above hydroxyacid (1.89 g;
8.22 mmol) and 4-amino-2-trifluoromethylbenzonitrile (2.05 g; 11.0 mol)
were in dry DMA (15 ml) under inert atmosphere. After the solution had been
cooled to -10°C, the thionyl chloride (0.75 ml; 10 mmol) was added slowly.
The reaction mixture was stirred for 15 min at -10°C and then the ice bath
was removed. After stirring overnight at room temperature, the reaction
mixture was deluted with CH2Cl2 and was extracted one time with saturated
NaHCO3. The organic layer was dried with MgSO4 and concentrated. The
product was purified by silica gel chromatography (6% ethyl acetate in
CH2Cl2). Yield 1.38 g (42%).
(2R)-N-[4-Cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-
hydroxy-2-methylpropanamide.
To a solution of the sulfide (1.27 g; 3.19 mmol) in CH2Cl2 (43 mL) was added
mCPBA (1.65 g; 9.57 mmol). After stirring overnight at room temperature,
the reaction mixture was diluted with ethyl acetate and extracted with Na2SO3
and NaHCO3 (2x). The organic layer was dried with MgSO4 and concentrated.
After purification by silica gel chromatography using a step gradient of ethyl
acetate in CHCl3, the product was obtained as white crystals from
benzene/petroleum ether. Yield 1.29 g (94%); ee>>99%; mp 178°C.
(2S)-N-[4-Cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-
hydroxy-2-methylpropanamide ee>>99%.
Product may be prepared from the starting materials. | [Brand name]
Casodex (AstraZeneca). | [Therapeutic Function]
Antitumor | [General Description]
Bicalutamide, N-4-cyano-3-(trifluoromethyl)phenyl-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methyl-propanamide (Casodex), is more potent than flutamideand has a much longer half-life (5.9 days vs. 6 hoursfor hydroxyflutamide). Because of the longer half-life, bicalutamideis used for once-a-day (50 mg) treatment of advancedprostate cancer. Bicalutamide is available as aracemic mixture, but both animal and human studies withthe AR show that the R-enantiomer has higher affinity forthe AR than the S-enantiomer. | [Biological Activity]
Orally active non-steroidal androgen receptor antagonist (IC 50 = 190 nM). Displays peripheral selectivity and does not effect serum levels of LH and testosterone. Exhibits potent anticancer activity in vivo . | [Biochem/physiol Actions]
Bicalutamide (CDX) is a non-steriodal Androgen Receptor (AR) antagonist and a pure antiandrogen. It acts via balancing histone acetylation/deacetylation and recruitment of coregulators. Bicalutamide (CDX) abolishes androgen-mediated expression. For example, MMP13 upregulation in prostate cancer, PLZF (promyelocytic leukemia zinc finger protein), and GADD45γ (growth arrest and DNA damage inducible, gamma). Bicalutamide (CDX) is inhibited by non-genomic, transcription-independent stimulation of PI3K/AKT phosphorylation by androgens. | [Mechanism of action]
Bicalutamide is a racemate and its antiandrogenic activity resides almost exclusively in the (R)-enantiomer, which has an approximately fourfold higher affinity for the prostate AR than hydroxyflutamide does. The (S)-enantiomer has no antiandrogenic activity. (R)-Bicalutamide is slowly absorbed, but absorption is unaffected by food. It has a long plasma elimination half-life of 1 week and accumulates approximately 10 times in plasma during daily administration. (S)-Bicalutamide is much more rapidly absorbed and cleared from plasma. At steady state, the plasma levels of (R)-bicalutamide are 100 times higher than those of (S)-bicalutamide. Although mild to moderate hepatic impairment does not affect pharmacokinetics, evidence suggests slower elimination of (R)-bicalutamide in subjects with severe hepatic impairment. | [Pharmacology]
Bicalutamide is a competitive AR antagonist, which shows in vitro a lower affinity for the AR as compared to the synthetic androgen R1881 as well as the natural DHT. However it displays a fourfold higher affinity as compared to hydroxyflutamide as assessed by a binding assay. Bicalutamide inhibits the growth of the LNCaP/FGC prostate carcinoma cell line, in which hydroxyflutamide was not effective at all. In vivo anti-androgenic activity of bicalutamide was confirmed by dose-dependent weight reduction of the seminal vesicles and ventrical prostate gland in rats, followed by an antitumor efficacy using Dunning R3327-GH prostate carcinomas in intact and castrated rats.A full overview on all clinical trials including bicalutamide would be out of scope. | [Clinical Use]
Bicalutamide is a nonsteroidal pure antiandrogen given at a dosage of 150 mg once daily as monotherapy for the treatment of early (localized or locally advanced) nonmetastatic prostate cancer. It also can be used at a lower dosage in combination with a LHRH analogue or surgical castration for the treatment of advanced prostate cancer. | [Side effects]
Bicalutamide was well tolerated in monotherapy as well as in combination. No dose-related increase in adverse events was reported. Adverse events were partially due to pharmacological effects of an anti-androgen, which include gynecomastia, breast tenderness, and hot flushes. Other non-pharmacological adverse events, with incidence equal or higher than 10% were, for example, constipation, nausea, diarrhea, asthenia, pain, and infection. The frequency of non-pharmacological adverse events was in the same range as reported for comparator in clinical trials. In contrast to flutamide, the incidence of diarrhea and liver abnormalities was much lower for bicalutamide. As compared with castration, monotherapy with bicalutamide allowed patients to maintain libido and have better physical capacity, thus resulting in better quality of life.Based on the results of the clinical trials mentioned above, bicalutamide was first approved in 1995. Bicalutamide is indicated for the use in combination with an LHRH-A analogue for metastatic prostate carcinoma (50mg). | [Drug interactions]
Potentially hazardous interactions with other drugs
Anticoagulants: possibly enhances anticoagulant
effect of coumarins.
Lipid lowering agents: separate lomitapide and
bicalutamide administration by 12 hours.
See 'Other information'. | [Metabolism]
Bicalutamide metabolites are excreted almost equally in urine and feces, with little or no unchanged drug excreted in urine. Unmetabolized drug predominates in the plasma. Following oral administration, the racemate displays stereoselective oxidative metabolism of its (R)-enantiomer, with an elimination half-life of approximately 6 days. (R)-Bicalutamide is cleared almost exclusively by CYP3A4-mediated metabolism, but glucuronidation is the predominant metabolic route for (S)-bicalutamide. | [storage]
Store at RT |
|
|