Bexarotene

Bexarotene

IUPAC: 4 - [1 - ( 3,5,5,8,8 - Pentamethyltetralin -2-yl ) ethenyl ] benzoic acid
SR- 11247
LGD -1069
Targretin (brand name)

L01XX25

White crystalline powder

Retinoids

Fixed

1.042 g · cm -3

230-231 ° C

Very slightly soluble in water (about 10 to 50 uM )
Soluble in ethanol (10 mg / ml)
Soluble in DMSO ( 65 mg / ml)

> 1500 mg · kg -1 ( LD50, rat, oral)
> 720 mg · kg -1 ( LD50, dog, oral)

Template: Infobox chemical / molecular formula search available

Bexarotene ( Targretin trade name, manufacturer Eisai ) is the international non-proprietary name for a synthetic retinoid analog that is approved for the treatment of cutaneous T -cell lymphoma. Sold it in Germany from Cephalon.

Clinical Application

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

The mechanism of action is not yet fully elucidated bexarotene. It specifically binds the retinoid to the retinoid X receptor ( RXR). The retinoid X receptors are transcription factors that affect cell proliferation and differentiation, and apoptosis, and insulin sensitizers. In in vitro experiments, an inhibition of proliferation in hematopoietic cells could be detected. In animal studies it caused tumor regression, ie a regression of malignant tumor.

Admission -border ( off- label use ) is bexarotene also used for the treatment of bronchial carcinoma.

Side effects

In the clinical trials for approval of bexarotene in the treatment of cutaneous T -cell lymphoma in particular the following adverse reactions were observed in the patients: hyperlipoproteinemia (especially triglycerides), 74% of patients, hypothyroidism ( 29%), hypercholesterolemia ( 28%), headache ( 27%), leukopenia (20 % ), itching (20%), asthenia ( 19%), rash ( 16%), exfoliative dermatitis ( 15%) and pain ( 12%).

Preclinical results on Alzheimer's disease

Caused a stir a February 9, 2012 article published in Science. In this publication, the potential effect of bexarotene in the animal model color mouse is described in Alzheimer 's disease. The administration of bexarotene eliminated in transgenic mice not only existing and typical for Alzheimer 's disease protein plaques that are to be the cause of Alzheimer's symptoms after the plaques theory, but also the memory disorders. Bexarotene can overcome a very non-polar and relatively small molecule cross the blood- brain barrier. There it influences the expression of apolipoprotein E, which is produced in large quantities and the reduction of senile plaques, mainly β -amyloid possible.

At present it is still unclear whether these results can also be transmitted to humans. The authors of the Science article pointed out that there are many known methods which can cure Alzheimer's in mice, but all did not work in humans.

For the treatment of Alzheimer's disease bexarotene is not permitted.

Synthesis

History of development

Bexarotene was developed by the U.S. company Ligand Pharmaceuticals, sold the Targretin and three other potential cancer therapeutics in 2006 for 205 million U.S. $ to the Japanese company Eisai. The product patent (see original product ) expire in 2016.