Cyclohexane 1,3-diones and their inhibition of mutant SOD1-dependent protein aggregation and toxicity in PC12 cells
| Autor: | Robert J. Ferrante, Wei Zhang, Radhia Benmohamed, Richard B. Silverman, Richard I. Morimoto, Anthony C. Arvanites, Donald R. Kirsch |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Cyclopropanes
Cell type Clinical Biochemistry SOD1 Pharmaceutical Science Mice Transgenic Protein aggregation Blood–brain barrier medicine.disease_cause PC12 Cells Biochemistry Article Superoxide dismutase Mice Superoxide Dismutase-1 Drug Discovery medicine Animals Humans Amyotrophic lateral sclerosis Molecular Biology Neurons Mutation biology Cyclohexanones Superoxide Dismutase Chemistry Phenyl Ethers Amyotrophic Lateral Sclerosis Organic Chemistry medicine.disease Rats Riluzole Disease Models Animal medicine.anatomical_structure Amino Acid Substitution Blood-Brain Barrier biology.protein Molecular Medicine medicine.drug |
| Zdroj: | Bioorganic & Medicinal Chemistry. 20:1029-1045 |
| ISSN: | 0968-0896 |
| Popis: | Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons. Currently, there is only one FDA-approved treatment for ALS (riluzole), and that drug only extends life, on average, by 2-3 months. Mutations in Cu/Zn superoxide dismutase (SOD1) are found in familial forms of the disease and have played an important role in the study of ALS pathophysiology. On the basis of their activity in a PC12-G93A-YFP high-throughput screening assay, several bioactive compounds have been identified and classified as cyclohexane-1,3-dione (CHD) derivatives. A concise and efficient synthetic route has been developed to provide diverse CHD analogs. The structural modification of the CHD scaffold led to the discovery of a more potent analog (26) with an EC(50) of 700 nM having good pharmacokinetic properties, such as high solubility, low human and mouse metabolic potential, and relatively good plasma stability. It was also found to efficiently penetrate the blood-brain barrier. However, compound 26 did not exhibit any significant life span extension in the ALS mouse model. It was found that, although 26 was active in PC12 cells, it had poor activity in other cell types, including primary cortical neurons, indicating that it can penetrate into the brain, but is not active in neuronal cells, potentially due to poor selective cell penetration. Further structural modification of the CHD scaffold was aimed at improving global cell activity as well as maintaining potency. Two new analogs (71 and 73) were synthesized, which had significantly enhanced cortical neuronal cell permeability, as well as similar potency to that of 26 in the PC12-G93A assay. These CHD analogs are being investigated further as novel therapeutic candidates for ALS. |
| Databáze: | OpenAIRE |
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