N-[4-cyano-3-(trifluoromethyl)phenyl]-3-(4-fluorobenzenesulfonyl)-2-hydroxy-2-methylpropanamide

• ChemBase ID: 999
• Molecular Formular: C18H14F4N2O4S
• Molecular Mass: 430.3733728
• Monoisotopic Mass: 430.06104082
• SMILES: S(=O)(=O)(CC(O)(C)C(=O)Nc1cc(c(cc1)C#N)C(F)(F)F)c1ccc(F)cc1
• Canonical SMILES: N#Cc1ccc(cc1C(F)(F)F)NC(=O)C(CS(=O)(=O)c1ccc(cc1)F)(O)C
• 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

NAMES AND DATABASE IDS

Names

• IUPAC name: N-[4-cyano-3-(trifluoromethyl)phenyl]-3-(4-fluorobenzenesulfonyl)-2-hydroxy-2-methylpropanamide; (2R)-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-(4-fluorobenzenesulfonyl)-2-hydroxy-2-methylpropanamide
• IUPAC Traditional name: N-[4-cyano-3-(trifluoromethyl)phenyl]-3-(4-fluorobenzenesulfonyl)-2-hydroxy-2-methylpropanamide; bicalutamide; (2R)-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-(4-fluorobenzenesulfonyl)-2-hydroxy-2-methylpropanamide
• Brand Name: Casodex
• Synonyms: Bicalutamide; N-[4-Cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide; Bicalutamide (CDX); 2-(1,2-Diphenylethoxy)-N,N,N-(trimethyl-d9)ethanaminium Bromide; [2-(1,2-Diphenylethoxy)ethyltrimethyl-d9]ammonium Bromide; ES 132-d9; Lysbex-d9; Lysibex-d9; Lysobex-d9; Medipectol-d9; OM-Tussic-d9; OM-Tussis-d9; Rea-tos-d9; Sedobex-d9; Thoragol-d9; Bibenzonium-d9 Bromide; Bicalutamide; (2r)-N-[4-Cyano-3-(Trifluoromethyl)Phenyl]-3-[(4-Fluorophenyl)Sulfonyl]-2-Hydroxy-2-Methylpropanamide; Casodex; Cosudex; Calutide; Kalumid; Bicalutamide(Casodex)

Database IDs

• CAS Number: 90357-06-5
• MDL Number: MFCD00869971
• PubChem SID: 46505386; 46506892; 160964462
• PubChem CID: 56069; 2375

CALCULATED PROPERTIES

JChem

• Acid pKa: 11.947144
• H Acceptors: 5
• H Donor: 2
• LogD (pH = 5.5): 2.7092955
• LogD (pH = 7.4): 2.7092834
• Log P: 2.7092955
• Molar Refractivity: 96.5895 cm^3
• Polarizability: 36.135174 Å^3
• Polar Surface Area: 107.26 Å^2
• Rotatable Bonds: 6
• Lipinski's Rule of Five: true

ALOGPS 2.1

• Log P: 2.7
• LOG S: -4.67
• Solubility (Water): 9.28e-03 g/l

PROPERTIES

Physical Property

• Solubility: 5 mg/L; DMSO; DMSO: >5 mg/mL; H2O: insoluble
• Apperance: powder
• Hydrophobicity(logP): 2.5

Safety Information

• Storage Condition: -20°C; desiccated; protect from light
• RTECS: TX1413500
• European Hazard Symbols: Irritant (Xi)
• German water hazard class: 3
• Risk Statements: 36/37/38
• Safety Statements: 26
• GHS Pictograms: GHS07
• GHS Signal Word: Warning
• GHS Hazard statements: H315-H319-H335
• GHS Precautionary statements: P261-P305 + P351 + P338
• Personal Protective Equipment: dust mask type N95 (US), Eyeshields, Gloves

Pharmacology Properties

• Target: androgen receptor
• Mechanism of Action: Antiandrogen; Prevent the action of androgens by blocking the receptors for androgens on the cells of tissues, for example, the cells of the prostate gland

Product Information

• Purity: ≥98% (HPLC)
• Salt Data: Free Base
• Application(s): Antiandrogen investigated for the treatment of advanced prostate cancer
• Empirical Formula (Hill Notation): C18H14F4N2O4S

DETAILS

DrugBank - DB02932

Drug information: experimental

DrugBank - DB01128

• Drug Groups: approved
• Description: Bicalutamide is an oral non-steroidal anti-androgen for prostate cancer. It binds to the androgen receptor.
• Indication: For treatment (together with surgery or LHRH analogue) of advanced prostatic cancer.
• Pharmacology: Bicalutamide is an antineoplastic hormonal agent primarily used in the treatment of prostate cancer. Bicalutamide is a pure, nonsteroidal anti-androgen with affinity for androgen receptors (but not for progestogen, estrogen, or glucocorticoid receptors). Consequently, Bicalutamide blocks the action of androgens of adrenal and testicular origin which stimulate the growth of normal and malignant prostatic tissue. Prostate cancer is mostly androgen-dependent and can be treated with surgical or chemical castration. To date, antiandrogen monotherapy has not consistently been shown to be equivalent to castration.
• Affected Organisms: Humans and other mammals
• Biotransformation: Bicalutamide undergoes stereo specific metabolism. The S (inactive) isomer is metabolized primarily by glucuronidation. The R (active) isomer also undergoes glucuronidation but is predominantly oxidized to an inactive metabolite followed by glucuronidation.
• Absorption: Bicalutamide is well-absorbed following oral administration, although the absolute bioavailability is unknown.
• Half Life: 5.9 days
• Protein Binding: 96%
• Clearance: * Apparent oral cl=0.32 L/h [Normal Males]
• External Links: Wikipedia; RxList; Drugs.com

Selleck Chemicals - S1190

Research Area

• Description: Endocrinology

Biological Activity

• Description: Bicalutamide (Casodex, Cosudex, Calutide, Kalumid) is an androgen receptor (AR) antagonist with IC50 of 0.16 μM.
• Targets: AR
• IC50: 0.16 μM ^[1]
• In Vitro: Bicalutamide undergoes an antagonist-to-agonist switch, stimulating AR activity. Bicalutamide treatment of LNCaP/AR(cs) cells in absence of the synthetic androgen R1881 results in altered gene expression consistent with its well-documented agonist activity in context of AR overexpression. Bicalutamide induces cell proliferation in a dose-dependent manner, and only partially antagonized the effects of R1881. Bicalutamide treatment also results in a significant amount of nuclear AR, although less than that observed with R1881. Bicalutamide exhibits partial agonist activity as evidenced by induction of DNA binding at AR target genes and incomplete antagonism of the effects of R1881. In absence of R1881, Bicalutamide partially activates VP16-AR–mediated transcription, indicative of AR binding to DNA. In LNCaP/AR-luc cells with a stably integrates AR-driven luciferase reporter construct. In the presence of R1881, Bicalutamide shows only weak partial antagonism of VP16-AR–mediated transcription with an IC50 of 0.35 μM. ^[1] Micromolar bicalutamide causes a significant dose-dependent reduction in clonogenicity. ^[2] Dual inhibition of the AR and mTOR signaling pathways provides further benefit with the ridaforolimus-bicalutamide combination producing syner -gistic antiproliferative effects in prostate cancer cells in vitro when compared with each agent alone. ^[3]
• In Vivo: Single bicalutamide reduces tumor growth by 79%, at defined submaximal doses. The ridaforolimus-bicalutamide combination exhibits improved and potent antitumor activity, almost completely abrogating tumor growth. The combination is also well tolerated, as evidenced by no significant changes in body weight over the course of treatment. Plasma PSA levels are again tightly linked to tumor growth in the combination-treated mice. ^[3]
• Clinical Trials: Bicalutamide plus MDV3100 has entered in a phase II clinical trial in the treatment of prostatic neoplasms.

Combination Therapy

• Description: Single Bicalutamide reduces tumor growth by 79%, at defined submaximal doses. The ridaforolimus-bicalutamide combination exhibits improved and potent antitumor activity, almost completely abrogating tumor growth. The combination is also well tolerated, as evidenced by no significant changes in body weight over the course of treatment. Plasma PSA levels are again tightly linked to tumor growth in the combination-treated mice. ^[3] Bicalutamide plus MDV3100 has entered in a phase II clinical trial in the treatment of prostatic neoplasms.

Protocol

• Protocol: Kinase Assay ^[1]
• Whole-cell competitive binding assays: Whole-cell competitive binding assays are performed in LNCaP/AR(codon-switch) (LNCaP/AR(cs)) (harbors a mixture of exogenous wild-type AR and endogenous mutant AR (T877A)) and cells propagated in Iscove’s or RPMI media supplemented with 10% fetal bovine serum, or during the assay with 10% charcoal-stripped, dextran-treated fetal bovine serum (CSS). Cells are pre-incubated with ^18F-FDHT, increasing concentrations (1pM to 1μM) of cold Bicalutamide are added, and the assay is performed to measure specific uptake of ^18F-FDHT (4). IC50 values are determined using a one site binding model with least squares curve fitting and R^2 > 0.99.
• Protocol: Cell Assay ^[3]
• Cell Lines: C4-2 cell
• Concentrations: 0-1 μM
• Incubation Time: 72 hours
• Methods: Exponentially growing C4-2 cells are plated into two 96-well plates and incubated overnight at 37 ?C. Twenty-four hours later one plate is aspirated and stored at -80 ?C and the other treated with 10-fold serial concentrations of ridaforolimus (1000 nM to 0.0001 nM) or vehicle (ethanol). Following 72 hours culture at 37 ?C, the plates are assessed simultaneously for cell growth using the Cy qUANT Cell Proliferation Assay kit. Bicalutamide and Ridaforolimus combination proliferation assays are performed similarly except cell growth is determined as the change in cell number between vehicle control and compound treated cells after 72 hours in culture.
• Protocol: Animal Study ^[3]
• Animal Models: Male nude mice bearing C4-2 cells
• Formulation: 4% ethanol, 5% Tween 80, and 5% propylene glycol
• Doses: 10 mg/kg
• Administration: Administered via p.o.

References

• References: [1] Clegg NJ, et al. Cancer Res. 2012, 72(6), 1494-1503.
• References: [2] Colquhoun AJ, et al. Prostate Cancer Prostatic Dis. 2012.
• References: [3] Squillace RM, et al. Int J Oncol. 2012.

Sigma Aldrich - B9061

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.

Toronto Research Chemicals - B373502

Labelled Bibenzonium bromide (B373500). Used for preparation of substituted indoles as cysteinyl leukotriene receptor modulators.

REFERENCES

• Clegg NJ, et al. Cancer Res. 2012, 72(6), 1494-1503.
• Colquhoun AJ, et al. Prostate Cancer Prostatic Dis. 2012.
• Squillace RM, et al. Int J Oncol. 2012.
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