Zhang, Wei; Benmohamed, Radhia; Arvanites, Anthony C.; Morimoto, Richard I.; Ferrante, Robert J.; Kirsch, Donald R.; Silverman, Richard B. published the artcile< Cyclohexane 1,3-diones and their inhibition of mutant SOD1-dependent protein aggregation and toxicity in PC12 cells>, Reference of 197638-83-8, the main research area is cyclohexanedione preparation inhibition mutant SOD1 dependent protein aggregation.
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 mo. 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 pathophysiol. 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 (I) with an EC50 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 I did not exhibit any significant life span extension in the ALS mouse model. It was found that, although I 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 (II and III) were synthesized, which had significantly enhanced cortical neuronal cell permeability, as well as similar potency to that of I in the PC12-G93A assay. These CHD analogs are being investigated further as novel therapeutic candidates for ALS.
Bioorganic & Medicinal Chemistry published new progress about Aggregation (protein). 197638-83-8 belongs to class piperazines, and the molecular formula is C16H22N2O3, Reference of 197638-83-8.
Referemce:
Piperazine – Wikipedia,
Piperazines – an overview | ScienceDirect Topics