Bexarotene

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Structural formula
Structure of bexarotene
General
Non-proprietary name Bexarotene
other names
  • 4- [1- (3,5,5,8,8-Pentamethyltetralin-2-yl) ethenyl] benzoic acid ( IUPAC )
  • SR-11247
  • LGD-1069
  • Targretin (brand name)
Molecular formula C 24 H 28 O 2
Brief description

white crystalline powder

External identifiers / databases
CAS number 153559-49-0
EC number 681-650-8
ECHA InfoCard 100.206.790
PubChem 82146
DrugBank DB00307
Wikidata Q418192
Drug information
ATC code

L01 XX25

Drug class

Retinoids

properties
Molar mass 348.48 g · mol -1
Physical state

firmly

Melting point

230-231 ° C

solubility
  • very poorly soluble in water (approx. 10 to 50 µM)
  • soluble in ethanol (10 mg / ml)
  • well soluble in DMSO (65 mg / ml)
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances
07 - Warning

Caution

H and P phrases H: 302-315-319-335
P: 261-280-305 + 351 + 338-304 + 340-362-301 + 312-312-405-403 + 233-501
Toxicological data
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Bexarotene (trade name Targretin ; Manufacturer Eisai ) is the international non-proprietary name for a synthetic retinoid - analogue , which for treatment of cutaneous T-cell lymphoma admitted is. It is distributed in Germany by Cephalon .

Clinical application

In the United States, in 1999, bexarotene was approved for oral use in the treatment of cutaneous T-cell lymphoma in patients who are no longer responding to prior systemic therapy, that is, are refractory. In Germany, it was approved as an orphan drug for this rare malignant skin disease in January 2002 . Again, it may only be used if at least one previous systemic treatment has not been effective and the disease is in an advanced stage.

The mechanism of action of bexarotene is not yet fully understood. As a retinoid, it binds specifically to the retinoid X receptor (RXR). The retinoid X receptors are transcription factors that influence cell proliferation and differentiation , as well as apoptosis and insulin sensitization. In in vitro - Try proliferation inhibition in hematopoietic cells could be detected. In animal experiments it caused tumor regression, that is, regression of the malignant tumor.

Bexarotene is also used for the treatment of bronchial carcinoma beyond the approval ( off-label use ) .

Side effects

In the clinical studies for the approval of bexarotene for the treatment of cutaneous T-cell lymphoma, the following side effects were found in the patients : hyperlipoproteinemia (mainly triglycerides ) 74% of patients, hypothyroidism (29%), hypercholesterolemia (28%), Headache (27%), leukopenia (20%), pruritus (20%), asthenia (19%), rash (16%), exfoliative dermatitis (15%) and pain (12%).

Preclinical results on Alzheimer's disease

An article published in Science on February 9, 2012 caused a stir . This publication describes the potential effect of bexarotene in the color mouse animal model in Alzheimer's disease . The administration of bexarotene in the transgenic mice eliminated not only the protein plaques that were present and typical of Alzheimer's disease , which, according to plaque theory, are the reason for the Alzheimer's symptoms, but also the memory disorders . As a very non-polar and relatively small molecule, bexarotene can cross the blood-brain barrier . There it influences the expression of apolipoprotein E , which is produced in large quantities and enables the breakdown of senile plaques , especially β-amyloid .

It is currently unclear whether these results can also be transferred to humans. The authors of the Science article pointed out that there are many known methods that can be used to cure Alzheimer's disease in mice, but none of them work in humans.

Subsequent pre-clinical trials by other research groups could not confirm the promising results.

Bexarotene is not approved for the treatment of Alzheimer's disease.

synthesis

Synthesis of bexarotene

Development history

Bexarotene was developed by the US company Ligand Pharmaceuticals , which sold Targretin and three other potential cancer therapeutics to the Japanese company Eisai in 2006 for US $ 205 million . The substance patent (see original preparation ) expired in 2016.

further reading

Individual evidence

  1. ↑ a b c d e f Material Safety Data Sheet - LC Laboratories Cat. No. B-2422. ( Memento of May 9, 2015 in the Internet Archive ) November 8, 2008.
  2. ↑ Entry on bexarotene. In: Römpp Online . Georg Thieme Verlag, accessed on February 26, 2016.
  3. ↑ a b Data sheet Bexarotene, 99 +% at AlfaAesar, accessed on November 1, 2016 ( PDF )(JavaScript required) .
  4. ↑ Yellow List ( Memento from July 31, 2012 in the web archive archive.today ), accessed on February 11, 2012.
  5. ↑ EMA: EPAR-Product Information (PDF; 264 kB), accessed on February 11, 2012.
  6. ↑ a b Bexarotene Targretin® soft capsules (Elan Pharma). In: Pharmaceutical newspaper. Retrieved February 10, 2012.
  7. ↑ H. Fritz, D. Kennedy et al.: Vitamin A and retinoid derivatives for lung cancer: a systematic review and meta analysis. In: PloS one. Volume 6, number 6, 2011, p. E21107, doi: 10.1371 / journal.pone.0021107 . PMID 21738614 . PMC 3124481 (free full text).
  8. ↑ Summary of Product Characteristics. (PDF; 264 kB) European Medicines Agency, accessed on February 10, 2012.
  9. ↑ PE Cramer, JR Cirrito et al: ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models. In: Science . doi: 10.1126 / science.1217697
  10. ↑ Active ingredient bexarotene eliminates memory disorders and protein plaques in mice. In: scinexx. 10 February 2012
  11. ^ E. O'Hare, R. Jeggo et al. a .: Lack of support for bexarotene as a treatment for Alzheimer's disease. In: Neuropharmacology. [Electronic publication before printing] May 2015, doi: 10.1016 / j.neuropharm.2015.04.020 , PMID 26025659 .
  12. ↑ C. Balducci, A. Paladini et al. a .: The Continuing Failure of Bexarotene in Alzheimer's Disease Mice. In: Journal of Alzheimer's disease: JAD. [Electronic publication before printing] March 2015, doi: 10.3233 / JAD-150029 , PMID 25777514 .
  13. ↑ B. Tousi: The emerging role of bexarotene in the treatment of Alzheimer's disease: evidence current. In: Neuropsychiatric disease and treatment. Volume 11, 2015, pp. 311-315, doi: 10.2147 / NDT.S61309 , PMID 25709453 , PMC 4327563 (free full text) (review).
  14. ↑ Patent US5780676 : Compounds having selective activity for Retinoid X Receptors, and means for modulation of processes mediated by Retinoid X Receptors. Filed June 7, 1995 , published July 14, 1998 , Applicants: Ligand Pharmaceuticals, Inventors: Marcus F. Boehm, Richard A. Heyman, Lin Zhi, Chan Kou Hwang, Steve White, Alex Nadzan. ‌
  15. ^ B. Glenn: CWRU researchers: Drug shows promise in reducing Alzheimer's plaque in brain. In: medcitynews.com of February 9, 2012.