Thalidomide Derivatives for the Treatment of Neuroinflammation

• Published in: ChemMedChem 2010-12, Vol.5 (12), p.2057-2064
• Main Authors: Contino-Pépin, Christiane, Parat, Audrey, Patinote, Cindy, Roscoe, Wendi A., Karlik, Stephen J., Pucci, Bernard
• Format: Article
• Language: English
• Subjects: Administration, Oral; angiogenesis; Animals; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental - drug therapy; Mice; Mice, Inbred C57BL; multiple sclerosis; Multiple Sclerosis - drug therapy; neuroinflammation; telomers; thalidomide; Thalidomide - analogs & derivatives; Thalidomide - chemical synthesis; Thalidomide - therapeutic use
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201000326

The precise mechanism‐of‐action of thalidomide remains uncertain and might differ between diseases and under different clinical condition. With implications in the treatment of a variety of inflammatory and autoimmune diseases, as well as for use as an anticancer agent, alone or in combination with established therapeutics, it is clear that thalidomide and its derivatives deserve further scrutiny. In particular, thalidomide was shown to be effective in a mouse model of multiple sclerosis (MS), an autoimmune inflammatory disorder, called experimental autoimmune encephalomyelitis (EAE). Herein, we describe the synthesis and preliminary biological evaluation of new macromolecular prodrugs of thalidomide bearing an aminoalkyl group on the phthalimide ring. The effectiveness of these compounds to limit EAE was investigated, and it was shown that, at 100 mg kg−1 thalidomide‐equivalent dose, they abrogated the clinical and pathological features of EAE. Teaching an old dog new tricks? Herein, we describe the synthesis and preliminary biological evaluation of new macromolecular prodrugs of thalidomide bearing an aminoalkyl group on the phthalimide ring. The effectiveness of these compounds to limit experimental allergic encephalomyelitis (EAE) was investigated, and we found that, at 100 mg kg−1 thalidomide equivalent dose, they abrogated the clinical and pathological features of EAE.