153559-49-0 Usage
Uses
Used in Pharmaceutical Industry:
Bexarotene is used as an antineoplastic agent for the treatment of refractory cutaneous T-cell lymphoma. It acts as a selective retinoid X receptor (RXR) agonist, inducing cell differentiation, apoptosis, and inhibiting cell proliferation in several models of cancer.
Used in Alzheimer's Disease Research:
Bexarotene is used as a potential therapeutic agent in Alzheimer's disease research. It has been shown to reduce increased brain interstitial fluid levels of amyloid-β (1-40) (Aβ40) and Aβ42 in the APP/PS1 transgenic mouse model of Alzheimer's disease, which may contribute to improved cognitive ability.
Used in Antiviral Applications:
Bexarotene is used as an antiviral agent against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It has demonstrated the ability to reduce viral load in the culture supernatant of Vero E6 cells infected with SARS-CoV-2 and inhibit SARS-CoV-2 replication in a plaque reduction assay.
Used in Oncology:
Bexarotene is used as a therapeutic agent in oncology, particularly for the treatment of cutaneous T-cell lymphoma. It induces apoptosis in various cutaneous T cell lymphoma (CTCL) cells and inhibits lung metastasis and angiogenesis in mouse xenograft models when administered at a specific dose.
Chemical Properties:
Bexarotene is a white solid with the brand name Targretin, manufactured by Ligand.
Originator
Ligand (US)
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.
Therapeutic Function
Antineoplastic
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.
Pharmacology
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
Side effects
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.
Drug interactions
Potentially hazardous interactions with other drugs
Antipsychotics: avoid with clozapine (increased risk
of agranulocytosis)
Lipid-regulating drugs: concentration increased by
gemfibrozil - avoid.
Metabolism
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
References
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
Check Digit Verification of cas no
The CAS Registry Mumber 153559-49-0 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,5,3,5,5 and 9 respectively; the second part has 2 digits, 4 and 9 respectively.
Calculate Digit Verification of CAS Registry Number 153559-49:
(8*1)+(7*5)+(6*3)+(5*5)+(4*5)+(3*9)+(2*4)+(1*9)=150
150 % 10 = 0
So 153559-49-0 is a valid CAS Registry Number.
InChI:InChI=1/C24H28O2/c1-15-13-20-21(24(5,6)12-11-23(20,3)4)14-19(15)16(2)17-7-9-18(10-8-17)22(25)26/h7-10,13-14H,2,11-12H2,1,3-6H3,(H,25,26)
153559-49-0Relevant articles and documents
Indolizines Enabling Rapid Uncaging of Alcohols and Carboxylic Acids by Red Light-Induced Photooxidation
Watanabe, Kenji,Terao, Nodoka,Kii, Isao,Nakagawa, Reiko,Niwa, Takashi,Hosoya, Takamitsu
supporting information, p. 5434 - 5438 (2020/07/24)
The irradiation of red light-emitting-diode light (λ = 660 nm) to 3-acyl-2-methoxyindolizines in the presence of a catalytic amount of methylene blue triggered the photooxidation of the indolizine ring, resulting in a nearly quantitative release of alcohols or carboxylic acids within a few minutes. The method was applicable for photouncaging various functional molecules such as a carboxylic anticancer drug and a phenolic fluorescent dye from the corresponding indolizine conjugates, including an insulin-indolizine-dye conjugate.
Carboxylation of Aryl Triflates with CO2 Merging Palladium and Visible-Light-Photoredox Catalysts
Bhunia, Samir Kumar,Das, Pritha,Nandi, Shantanu,Jana, Ranjan
, p. 4632 - 4637 (2019/06/27)
We report herein a visible-light-promoted, highly practical carboxylation of readily accessible aryl triflates at ambient temperature and a balloon pressure of CO2 by the combined use of palladium and photoredox Ir(III) catalysts. Strikingly, the stoichiometric metallic reductant is replaced by a nonmetallic amine reductant providing an environmentally benign carboxylation process. In addition, one-pot synthesis of a carboxylic acid directly from phenol and modification of estrone and concise synthesis of pharmaceutical drugs adapalene and bexarotene have been accomplished via late-stage carboxylation reaction. Furthermore, a parallel decarboxylation-carboxylation reaction has been demonstrated in an H-type closed vessel that is an interesting concept for the strategic sector. Spectroscopic and spectroelectrochemical studies indicated electron transfer from the Ir(III)/DIPEA combination to generate aryl carboxylate and Pd(0) for catalytic turnover.
Toward a Greener Barluenga-Valdés Cross-Coupling: Microwave-Promoted C-C Bond Formation with a Pd/PEG/H2O Recyclable Catalytic System
Lamaa, Diana,Messe, Estelle,Gandon, Vincent,Alami, Mouad,Hamze, Abdallah
, p. 8708 - 8712 (2019/11/03)
A green Barluenga-Valdés cross-coupling reaction for the synthesis of 1,1-diarylethylenes using palladium catalysis has been developed. The new catalytic system based on Pd/Xphos-SO3Na or Pd/MeDavephos-CF3SO3 in PEG/H2O under microwave irradiation was found to be the best conditions for this transformation. The recyclability of the palladium catalyst system was also studied, and it was found to be active over nine runs without significant loss in its activity.
Copper-catalyzed α-selective hydrostannylation of alkynes for the synthesis of branched alkenylstannanes
Yoshida,Shinke,Kawano,Takaki
, p. 10616 - 10619 (2015/06/30)
A variety of branched alkenylstannanes can directly be synthesized with excellent α-selectivity by the copper-catalyzed hydrostannylation using a distannane or a silylstannane, irrespective of the electronic and steric characteristics of terminal alkynes employed. Synthetic utility of the resulting branched alkenylstannane has been demonstrated by the total synthesis of bexarotene.
Selective arylation and vinylation at the α position of vinylarenes
Zou, Yinjun,Qin, Liena,Ren, Xinfeng,Lu, Yunpeng,Li, Yongxin,Zhou, Jianrong
, p. 3504 - 3511 (2013/07/05)
In intermolecular Heck reactions of styrene and vinylarenes, the aryl and vinyl groups routinely insert at the β position. However, selective insertion at the α position has been very rare. Herein, we provide a missing piece in the palette of Heck reaction, which gave >20:1 α selectivity. The key to our success is a new ferrocene 1,1′-bisphosphane (dnpf) that carries 1-naphthyl groups. Our mechanistic studies revealed that the high α selectivity is partly attributable to the steric effect of dnpf. The rigid and bulky 1-naphthyl groups of dnpf sterically disfavor β insertion. What the Heck! In intermolecular Heck reactions, insertion at the β position of aromatic olefins is very common, but reversal of the selectivity for selective α insertion has been a longstanding problem. A general method to couple aryl and vinyl triflates with aromatic olefins in >20:1 α selectivity is presented. The key to this successful approach is a new ferrocene bisphosphane with naphthyl groups on the phosphorus atom (see scheme; OTf=triflate). Copyright
PROCESS FOR THE PREPARATION OF HIGHLY PURE BEXAROTENE
-
, (2011/12/02)
The present invention provides an improved process for the preparation of highly pure bexarotene of formula (I). The present invention also provides impurities of bexarotene, method of isolation and identification of these impurities, and use of these impurities as reference marker as well as reference standard.
NOVEL BEXAROTENE ANALOGS
-
, (2011/09/19)
The present invention relates to analogs of bexarotene and methods of use thereof.
Modeling, synthesis and biological evaluation of potential Retinoid X Receptor (RXR) selective agonists: Novel analogues of 4-[1-(3,5,5,8,8- pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene)
Wagner, Carl E.,Jurutka, Peter W.,Marshall, Pamela A.,Groy, Thomas L.,Van Der Vaart, Arjan,Ziller, Joseph W.,Furmick, Julie K.,Graeber, Mark E.,Matro, Erik,Miguel, Belinda V.,Tran, Ivy T.,Kwon, Jungeun,Tedeschi, Jamie N.,Moosavi, Shahram,Danishyar, Amina,Philp, Joshua S.,Khamees, Reina O.,Jackson, Jevon N.,Grupe, Darci K.,Badshah, Syed L.,Hart, Justin W.
experimental part, p. 5950 - 5966 (2010/02/28)
This report describes the synthesis of analogues of 4-[1-(3,5,5,8,8- pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (1), commonly known as bexarotene, and their analysis in acting as retinoid X receptor (RXR)-specific agonists. Compound 1 has FDA approval to treat cutaneous T-cell lymphoma (CTCL); however, its use can cause side effects such as hypothyroidism and increased triglyceride concentrations, presumably by disruption of RXR heterodimerization with other nuclear receptors. The novel analogues in the present study have been evaluated forRXR activation in an RXR mammalian-2-hybrid assay as well as an RXRE-mediated transcriptional assay and for their ability to induce apoptosis as well as for their mutagenicity and cytotoxicity. Analysis of 11 novel compounds revealed the discovery of three analogues that best induce RXR-mediated transcriptional activity, stimulate apoptosis, have comparable Ki and EC50 values to 1, and are selective RXR agonists. Our experimental approach suggests that rational drug design can develop new rexinoids with improved biological properties. 2009 American Chemical Society.
USE OF SUBSTITUTED 2 PHENYLBENZIMIDAZOLES AS MEDICAMENTS
-
, (2008/06/13)
The present invention relates to the use of a substituted 2-phenylbenzimidazole of formula I wherein R1, R2, R3, R 4, R5 and m have the meanings given in the claims, for the preparation of a medicament for the treatment or prevention of diseases involving glucagon receptors, as well as new compounds of formula I wherein R1 is a group of formula
ABC EXPRESSION PROMOTERS
-
, (2008/06/13)
The ABCA1 mRNA expression-promoting agent, LXRα mRNA expression-promoting agent, ABCG1 mRNA expression-promoting agent, cholesterol efflux-promoting agent, cholesteryl ester accumulation-inhibiting agent, ACAT-1 mRNA expression-inhibiting agent and CEH mRNA expression-promoting agent of the present invention are excellent in the ability to control cholesterol distribution in the body and have low toxicity.
