90357-06-5

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.

Off-White Crystalline Solid

Zeneca (United Kingdom)

adrenocortical suppressant, antineoplastic, steroid biosynthesis inhibitor

Non-steroidal peripherally active antiandrogen. Used as an antiandrogen, antineoplastic (hormonal)

ChEBI: A sulfone that is an oral non-steroidal antiandrogen used in the treatment of prostate cancer and hirsutism.

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.

[(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.

Casodex (AstraZeneca).

Antitumor

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.

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 .

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.

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.

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.

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.

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).

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'.

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.

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