May 12, 2014
Inducing neurogenesis may combat neurological diseases. Promoting neurogenesis in the adult brain may be a viable pathway for treating neurodegenerative and neuropsychiatric diseases, such as schizophrenia, Parkinson’s disease, and other conditions and diseases (see box).
Neurogenesis, the conversion of stem cells into functioning neurons, occurs primarily in two areas of the brain: the subventricular zone of the lateral ventricles and the subgranular zone of the dentate gyrus of the hippocampus. Under normal physiological conditions, neurogenesis in other regions of the central nervous system is very limited. But scientists believe that neurogenesis could be induced after stroke or traumatic brain injury.
Some researchers suggest that hippocampal adult neurogenesis is an important contributor to cognitive and emotional states, but the precise mechanism of this effect is a mystery. Recent research shows a correlation of physical exercise, exposure to an enriched environment, and antidepressant use with an increase in adult hippocampal neurogenesis. Chronic stress, depression, sleep deprivation, and aging are similarly correlated with decreased adult neurogenesis and negative cognitive and/or emotional states.
S. Ceccarelli and co-inventors describe a series of compounds capable of inducing neurogenesis that may be useful for treating or preventing neurodegenerative and neuropsychiatric diseases.
The compounds fall into two structural classes: piperazinone[1,2-a]indol-1-ones (1) and [1,4]diazepino[1,2-a]indol-1-ones (2) (see figure). The inventors prepared almost 300 examples of these structures and tested them with the neural stem cell proliferation assay. Several, including the ones listed in the figure, had EC50 values below 10 nM.
EC50 is the half-maximal effective concentration: the concentration of the compound at which 50% of the targeted population (in this case, neural stem cells) responds to treatment. Low values indicate that the compound may be highly efficacious.
The results indicate that many of the compounds of this invention could evolve into drugs that convert hippocampal stem cells to neurons and combat neurodegenerative and neuropsychiatric conditions and diseases. (Hoffmann-La Roche. WIPO Publication 2014023674, Feb.13, 2014; Benjamin Blass)
This patent was originally reviewed in ACS Medicinal Chemistry Letters.