Bexarotene 153559-49-0

Medical uses

Bexarotene is indicated for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma in people who are refractory to at least one prior systemic therapy (oral) and for the topical treatment of cutaneous lesions in patients with CTCL who have refractory or persistent disease after other therapies or who have not tolerated other therapies (topical).

Mechanism

Bexarotene is a retinoid specifically selective for retinoid X receptors, as opposed to the retinoic acid receptors. RXRs are located primarily in visceral organs such as the liver and kidney. Activated RXRs form homodimers or heterodimers with retinoic acid receptors, vitamin D receptors, thyroid receptors or peroxisome proliferator-activated receptors. Once activated, these retinoid receptor dimers bind to DNA at retinoic acid response elements and act as transcription factors that regulate the expression of genes which control cellular differentiation and proliferation. Retinoid agonists can activate the expression of retinoid regulated genes by removing negative transcription control or by facilitating positive transcriptional activity. They exert anticancer action by interfering with the growth of cells of the tumor.

Physical properties

Bexarotene is a solid, white powder. It is poorly soluble in water; the solubility is estimated to be about 10-50 µM. It is soluble in DMSO at 65 mg/mL and in ethanol at 10 mg/mL with warming.

Origin and development

History

The developer of bexarotene (brand name Targretin) was Ligand Pharmaceuticals, a San Diego biotech company which received FDA approval for the drug in 1999. Japanese pharmaceutical Eisai bought the rights to Targretin and three other anti-cancer products from Ligand in 2006. that researchers had discovered that bexarotene reduced amyloid plaque and improved mental functioning in a small sample of mice engineered to exhibit Alzheimer's symptoms. Three different mouse models (APP/PS1, APPPS1-21, Tg2576) were used. It is thought that bexarotene stimulates expression of apolipoprotein E (ApoE), which leads to intracellular clearance of β-Amyloid. The authors of the research article cautioned, "We've fixed Alzheimer's in mice lots of times, so we need to move forward expeditiously but cautiously," and hoped to start human trials soon. The chief executive of the Alzheimer's Foundation of America expressed concern that people desperate to find a treatment for Alzheimer's not take matters into "their own hands" or rush to take the medication.

Chemical synthesis

500pxM. F. Boehm, R. A. Heyman, L. Zhi, C. K. Hwang, S. White, A. Nadzan, (1998).