3-substituted indolones as novel therapeutic compounds for neurodegenerative conditions

October 29, 2008

Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS), disrupt the quality of life for patients, put a tremendous burden on family caregivers, and cost society billions of dollars annually. The most consistent risk factor for developing neurodegenerative disease is aging. Because of the dramatic increase in life expectancy, the incidence of individuals afflicted with the aging-associated disorders is on the rise representing a major health problem. A commonality shared among this diverse set of disorders is the progressive and relentless loss of certain populations of neurons. Current medications for neurodegenerative diseases alleviate only the symptoms associated with these diseases but do not affect the underlying cause - degeneration of neurons. Because neuronal loss continues unabated, such palliative treatments have no effect on disease progression. The identification of small-molecule inhibitors of neuronal death is thus of urgent and critical importance.

In the November issue of EBM, researchers at the University of Texas at Dallas and Southern Methodist University have identified a class of compounds, 3-substituted indolones, that can protect neurons from degeneration. Furthermore, the group has conducted a structure-activity relationship study to identify substituent groups that are important for neuroprotective efficacy. A previous study by the same group demonstrated that one of these 3-substituted indolones, called GW5074, prevents neurodegeneration and improves behavioral outcome in a mouse model of neurodegeneration. The senior author, Dr. Santosh D'Mello said "More recent but unpublished work by our group and Doris Kretzschmar, a collaborator at the Oregon Health and Science University, found that GW5074 and other related 3-substituted indolones are also protective in a fly model of Alzheimer's disease. " The current study identifies several compounds that are more efficacious than GW5074 and that display no cytotoxicity even when used at high doses. These 3-substituted indolones are thus novel and promising candidate therapeutic agents for pre-clinical testing against human neurodegenerative conditions. According to Dr. D'Mello, "Studies into the mechanisms underlying neuronal apoptosis has identified several molecules that can be targeted in developing drugs to treat neurodegenerative diseases. Some of these have been tested in human clinical studies but have not proven to be effective at reducing neurodegeneration in patients. Our study has identified some 3-substituted indolones that might be suitable for development as therapeutic agents. The structure-activity relationship analysis we have described in our report, although not exhaustive, also provides useful information on which other efficacious 3-substituted indolones can be synthesized and tested in pre-clinical and clinical studies".

Dr. Steven R. Goodman, Editor-in-Chief of Experimental Biology and Medicine, said "The work by D'Mello and colleagues has provided the basis for testing new versions of 3-substituted indolones for efficacy in the treatment of Alzheimer's disease and other neurodegenerative disorders. These drugs provide promising new therapeutic approaches to deal with the underlying cause of these disorders: neuronal cell death."

Society for Experimental Biology and Medicine

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