Bexarotene

Gefahreninformationscode (GHS)

• Bildanzeige (GHS)

  

• Alarmwort

  Warnung

• Gefahrenhinweise

  H302：Gesundheitsschädlich bei Verschlucken.

  H315：Verursacht Hautreizungen.

  H319：Verursacht schwere Augenreizung.

  H335：Kann die Atemwege reizen.

• Sicherheit

  P261：Einatmen von Staub vermeiden.

  P304+P340：BEI EINATMEN: Die Person an die frische Luft bringen und für ungehinderte Atmung sorgen.

  P305+P351+P338：BEI KONTAKT MIT DEN AUGEN: Einige Minuten lang behutsam mit Wasser spülen. Eventuell vorhandene Kontaktlinsen nach Möglichkeit entfernen. Weiter spülen.

  P405：Unter Verschluss aufbewahren.

Bexarotene Chemische Eigenschaften,Einsatz,Produktion Methoden

• Beschreibung

  Bexarotene was launched in the US for the treatment of manifestations of cutaneous T-cell lymphoma in patients who are refractory to at least one prior systemic therapy. The four step synthesis of bexarotene involves a double Friedel-Craft alkylation of toluene with 2,5-dichloro-2,5-dimethylhexane followed by acylation with monomethylterephthalic acid chloride, then Wittig methylidenation. Bexarotene is the first retinoid X receptor (RXR) agonist to be selective versus retinoid A receptors (RAR). Its activation of the three RXRα, β, γ isoforms induces cell differentiation and apoptosis and inhibits cell proliferation in several models of cancer. In phase ll/lll clinical trials, 48% of patients with refractory or persistent early-stage cutaneous T-cell lymphoma achieved a complete or partial response when treated with 300 mg/m2/day of bexarotene. It was shown in phase I trials that this second-generation retinoid was substantially less toxic than the broad-spectrum or RARselective retinoids.

• Beschreibung

  Bexarotene is an agonist of retinoid X receptors (RXRs; EC₅₀s = 28, 25, and 20 nM for RXRα, RXRβ, and RXRγ, respectively, in reporter assays). It is selective for RXRs over retinoic acid receptors (RARs; EC₅₀s = >10 μM for RARα, RARβ, and RARγ). Bexarotene (10 μM) induces apoptosis in MJ, HuT 78, and HH cutaneous T cell lymphoma (CTCL) cells, as well as inhibits lung metastasis and angiogenesis in A549 and MDA-MB-231 mouse xenograft models when administered at a dose of 100 mg/kg per day. It reduces increased brain interstitial fluid levels of amyloid-β (1-40) (Aβ40) and Aβ42 in the APP/PS1 transgenic mouse model of Alzheimer’s disease. It also reduces viral load in the culture supernatant of Vero E6 cells infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; EC₉₀ = 9.4 μM) and inhibits SARS-CoV-2 replication in a plaque reduction assay (EC₅₀ = 2.01 μM). Formulations containing bexarotene have been used in the treatment of CTCL.

• Chemische Eigenschaften

  White Solid

• Originator

  Ligand (US)

• Verwenden

  Bexarotene is used as a Synthetic retinoid analog with specific affinity for the retinoid X receptor, an antineoplastic agent, already approved as an oral antineoplastic agent for cutaneous T cell lymphoma and being investigated against other cancers. A study has found that bexarotene in a mouse Alzheimer?s model lowered the most toxic form of β-amyloid peptide and increased cognitive ability.

• Verwenden

  Used as an antineoplastic. A selective retinoid X receptor (RXR) agonist

• Definition

  ChEBI: Bexarotene is a retinoid, a member of benzoic acids and a member of naphthalenes. It has a role as an antineoplastic agent.

• Indications

  Bexarotene (Targretin) belongs to a subclass of retinoids that selectively bind to and activates retinoid X receptors (RXRs), which have biological properties distinct from those of RARs. In vitro, bexarotene exerts antiproliferative effects on some tumor lines of hematopoietic and squamous cell origin.

• Manufacturing Process

  (a) Methyl [4-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) carbonyl]benzoate (1):
  To a suspension of aluminum chloride (1.10 g, 8.25 mmol) in 30 mL of 1,2- dichloroethane under argon at room temperature was added a solution of 1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalene (1.52 g, 7.5 mmol) (Kagechika, H. et al., J. Med. Chem, 31:2182 (1988)) and 4- carbomethoxybenzoyl chloride (1.57 g, 7.87 mmol) in 15 mL of 1,2-dichloroethane. The reaction mixture was stirred overnight and poured onto ice water and extracted with 40% ethyl acetate/hexane. The combined organic layers were washed with saturated aqueous NaHCO3and brine. The solution was dried over anhydrous MgSO4, filtered and concentrated to afford a brown solid (2.56 g). Flash chromatography (60% dichloromethane/hexane) yielded the desired product (1) as a white, crystalline solid (1.733 g, 64 %): m.p. 146°-149°C; Rf 0.11 (50% CH2Cl2/hexane). The structure of the product was also confirmed using IR, 1H NMR and mass spectroscopy.
  (b) [4-(5,6,7,8-Tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) carbonyl]benzoic acid (2):
  To a suspension of the ester (1) (0.120 g, 0.329 mmol) in 75% aqueous methanol (2 mL) was added potassium hydroxide (0.055 g). The reaction mixture was stirred at 60°C for 1 h during which time the material dissolved. The solution was cooled to room temperature, acidified with 1 N aqueous hydrochloric acid, and then extracted with 80% ethyl acetate/hexane. The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated to afford a white solid (0.109 g). Recrystallization from benzene/hexane afforded (2) as a white, crystalline solid (0.102 g, 89%): m.p. 209°-212°C. The structure of the product was also confirmed using IR, 1H NMR and mass spectroscopy.
  (c) Methyl 4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)-1- ethenyl]benzoate (3):
  To a suspension of methyltriphenylphosphonium bromide (0.196 g, 0.55 mmol) in 1 mL of benzene under argon at room temperature was added a 0.5 M solution of potassium hexamethyldisilazide in toluene (1.2 mL, 0.6 mmol), and the yellow solution was stirred for 5 min. A solution of keto-ester (1) (0.1 g, 0.274 mmol) in 1.5 mL of benzene was added and the orange solution was stirred for 3 h at room temperature. The reaction mixture was filtered through a plug of silica gel with 40% ethyl acetate/hexane. The filtrate was concentrated to afford a solid. Flash chromatography (30%; 40% dichloromethane/hexane) yielded the desired product (3) as a white solid (0.077 g, 78%): m.p. 167°-168°C; Rf 0.4 (50% dichloromethane/hexane). The structure of the product was also confirmed using IR, 1H NMR and mass spectroscopy.
  (d) [4-[1-(5,6,7,8-Tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)-1- ethenyl]benzoic acid (4):
  To a suspension of the ester (3) (0.058 g, 0.16 mmol) in 75% aqueous methanol (2 mL) was added one pellet of potassium hydroxide (0.1 g). The mixture was stirred at 70°C for 1 h during which time the material dissolved. The solution was cooled to room temperature, acidified with 1 N aqueous hydrochloric acid and then extracted with 80% ethyl acetate/hexane. The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated to afford a white solid. Recrystallization from dichloromethane/hexane afforded the desired acid (4) as a white, crystalline solid (42 mg, 91%): melting point 230°-231°C. The structure of the product was also confirmed using IR, 1H NMR and mass spectroscopy.

• Trademarks

  Targretin (Ligand).

• Therapeutic Function

  Antineoplastic

• Allgemeine Beschreibung

  Bexarotene is available in 75-mg capsules for oral administrationin the treatment of refractory cutaneous T-cell lymphoma.The agent is also available as a gel that may be usedtopically. The mechanism of action has not been fully establishedbut is thought to involve binding to retinoid receptorsresulting ultimately in the formation of transcription factorsthat promote cell differentiation and regulate cellular proliferation.168 Bexarotene has been demonstrated to activateapoptosis as a result of stimulation of caspase 3 and inhibitionof survivin, an antiapoptotic protein that would normallyinhibit caspase activity.Apoptosis is also stimulatedbecause of cleavage of poly(ADP-Ribose) polymerase,which is antiapoptotic. Reduced expression of the retinoidreceptor subtypes RXR and RAR has also been demonstratedfor the agent. Absorption is nearly complete afteroral administration and plasma protein binding is high(＜99%).There is extensive metabolism in the liver togive 6- and 7-hydroxy-bexarotene and 6- and 7-oxobexaroteneas well as glucuronides of these metabolites andthe parent. Elimination occurs via the feces with an eliminationhalf-life of 7 hours. Adverse effects include hypercholesterolemia,hypertriglyceridemia, hypothyroidism, myelosuppression,nausea, and skin rash.

• Biochem/physiol Actions

  Bexarotene is a highly selective retinoid X receptor (RXR) agonist. It is an antineoplastic agent, already approved as an oral antineoplastic agent for cutaneous T cell lymphoma and being investigated against other cancers. A study has found that bexarotene in a mouse Alzheimer′s model lowered the most toxic form of β-amyloid peptide and increased cognitive ability. The activity in the mouse Alzheimer′s models are believed to be by activating PPARγ:RXR and LXR:RXR dimers which induces the expression of apoE and facilitates Aβ clearance and promotes microglial phagocytosis.

• Pharmakologie

  Bexarotene is available in oral and topical formulations. Peak plasma levels are achieved within 2 hours of oral administration, although higher levels are obtained when the drug is ingested with a fatty meal. It is thought to be metabolized primarily by the hepatobiliary system, with a terminal half-life of approximately 7 hours. Topical and oral bexarotene are approved for earlystage (patch and plaque) cutaneous T-cell lymphoma that is refractory to at least one other therapy. Oral bexarotene is also approved for refractory cases of advanced disease; however, the best response has been noted in early disease. Local irritation, such as burning, pruritus, and irritant contact dermatitis, is common following topical application.

• Clinical Use

  Antineoplastic agent:
  
  Treatment of skin manifestations of cutaneous T-cell lymphoma

• Nebenwirkungen

  Major side effects seen after systemic administration include dyslipidemia, leukopenia, liver function test abnormalities, and possibly development of cataracts. Unlike other systemic retinoids, oral bexarotene causes thyroid abnormalities in approximately half of patients, which may necessitate treatment for hypothyroidism. Bexarotene is teratogenic and should not be prescribed in topical or oral form to women of childbearing potential unless a negative serum pregnancy test has been obtained and the patient agrees in writing to use two effective forms of contraception from 1 month before to 1 month after treatment.

• Arzneimittelwechselwirkung

  Potentially hazardous interactions with other drugs
  Antipsychotics: avoid with clozapine (increased risk of agranulocytosis)
  Lipid-regulating drugs: concentration increased by gemfibrozil - avoid.

• Stoffwechsel

  Hepatic metabolism. Studies suggest glucuronidation as a metabolic pathway, and that cytochrome P450 3A4 is the major cytochrome P450 isozyme responsible for formation of the oxidative metabolites. Bexarotene metabolites have little pharmacological activity. No studies have been done in renal failure although the pharmacokinetic data indicates that renal elimination is a minor excretory pathway

• Lager

  Store at +4°C

• Einzelnachweise

  1) Boehm et al. (1995), Design and synthesis of potent retinoid X receptor selective ligands that induce apoptosis in leukemia cells; J. Med. Chem., 38 3146 2) Gniadecki et al. (2007), The optimal use of bexarotene in cutaneous T-cell lymphoma; Br. J. Dermatol., 157 433 3) Bischoff et al. (1998), Beyond tamoxifen: the retinoid X receptor-selective ligand LGD1069 (TARGRETIN) causes complete regression of mammary carcinoma; Cancer Res., 58 479 4) Cramer et al. (2012), ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models; Science, 335 1503 5) Boehm-Cagan and Michaelson (2014), Reversal of apoE4-driven brain pathology and behavioral deficits by bexarotene; J. Neurosci., 34 7293

Bexarotene Upstream-Materialien And Downstream Produkte

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