Bibliographic
Curcumin is a curry spice with multiple biological activities that is also effective in transgenic AD mouse models. To improve the potency and pharmacokinetic properties of curcumin, the authors synthesized a series of hybrid molecules between curcumin and cyclohexyl-bisphenol A (CBA), a compound that has neurotrophic activity which curcumin lacks. The best compound from this initial synthesis was CNB-001, a molecule that has improved stability over curcumin and that is neuroprotective in multiple neurotoxicity assays in which curcumin is inactive. Next, the authors generated a large number of derivatives of CNB-001 and selected the best compound on the basis of activity in our multiple toxicity assays. The result was a much more potent molecule called J147. Further experimentation found that J147 was broadly neuroprotective compound with memory enhancing activity in aged rodents as well as AD transgenic mice. The neurotrophic and memory-enhancing activities of J147 were found to be associated with an increase in brain derived neurotrophic factor (BDNF) levels and the expression of BDNF responsive proteins, enhancement of LTP, synaptic protein preservation, the reduction of markers for oxidative stress and inflammation, the reduction of amyloid plaques, and lower levels of soluble Aβ1–42 and Aβ1–40. Therefore, the range of biological activities of J147 relevant to human AD is also much more extensive than any of the compounds that have failed in clinical trials. In addition, J147 is very potent, has good medicinal chemical properties for a CNS drug, is apparently safe, and is orally active. Thus, J147 is an exciting new compound with the potential to be an AD therapeutic by slowing disease progression through neuroprotection as well as providing immediate cognition benefits.