Jerrydylan, Concerning why high impacts are taking seemingly forever to develop, some backround -
Upregulating glutamate pathways in the brain was not widely pursued years ago because just about everyone thought it would by definition lead to horrendous excitotoxicity. Overactive glutamatergic pathways were known to be associated with epileptic seizures, and with glutamate toxicity in stroke and traumatic brain injury, as cellular damage released excess calcium ions into the surrounding tissues. So it was generally believed that upregulating glutamate/AMPA pathways would almost certainly induce excitotoxicity / seizures.
Dr. Lynch was the lone voice in the wilderness - he believed that there might be a way to upregulate glutamate pathways safely, and Dr. Rogers helped him design the compounds to do it, beginning with the structure of aniracetam (a pyrrolidinone) and building from there. Over a period of years, Cortex was able to assemble its broad use patent estate and vast compound library chiefly because no one else in the pharma world believed it could work.
Cyclothiazide was also known to have the ability to upregulate AMPA activity, and Lilly got into the act with their biarylpropylsulfonamide compounds, and Servier with benzothiadiazines, both structurally related to cyclothiazide.
As it turned out, the cyclothiazide related compounds did tend to cause excitotoxicity. However, Cortex had some compounds that were able to upregulate AMPA activity without causing excitotoxicity - the "low impact" group of compounds like CX-691/Org-24448 and CX-717. No other company appears to have anything like these. Cortex also was spending a lot of time developing high impacts, but decided to advance the low impacts first clinically since they appeared far safer. Lack of money has always dogged Cortex from the beginning though, so it hasn't been possible to optimally fund both high and low impact programs over the years.
The plot thickens however, since it was found that while the low impacts upregulate AMPA activity in the hippocampus and thus improve memory/cognition, it take a high impact to significantly upregulate brain neurotrophic factors like BDNF, which are key to neuroprotection / neuroregeneration. But while the high impacts have enormous clinical potential in treating neurodegenerative diseases, they tend to be associated with excitotoxicity, and therein lies the rub.
So besides inadequate funding, there are lots of science related obstacles to overcome with the high impact approach. Not only is there excitotoxicity, but there is also the feedback loop phenomenon, which causes upregulated BDNF levels to drop back to normal after prolonged dosing with a high impact. Using intermittent burst dosing with a short acting high impact compound, we may be able to get around this feedback loop problem, but this all takes lots of time and money - something chronically in short supply at Cortex, unfortunately.
