Development of patented tricyclic pyrones molecules for the treatment of Alzheimer?s Disease - 7. Project Summary/Abstract
Alzheimer’s disease (AD) afflicts approximately 44 million people worldwide and is the most common cause of
dementia in the elderly. There is an unmet medical need for the development of new Alzheimer’s disease
therapeutics. Amyloid- (A) deposited in the Alzheimer’s diseased brain has been hypothesized to initiate a
cascade of molecular changes leading to synaptic dysfunction, inflammation, and neuronal death. Therefore,
designing therapies targeting A and downstream events have become major strategies in Alzheimer’s disease
drug development. We have taken a rational design approach and synthesized a class of tricyclic pyrone
compounds (TPs) that show potent cell protection against A toxicity.
In our completed SBIR Phase I project, the lead compounds CP2 and TP70 were found to have high oral
bioavailability, excellent blood–brain barrier permeability, and low toxicity. Administering compounds orally to
young Alzheimer’s disease transgenic mouse models in a “preventive trial” resulted in substantially reduced
soluble and insoluble A species in the brain and preserved memory and motor function. Furthermore, we have
found that the lead TPs decreased both intraneuronal and extracellular Aβ aggregates as well as
hyperphosphorylated tau (p-tau), restored axonal trafficking, and modulated hippocampal synaptic
NMDA-mediated activity and plasticity — these multiple synergistic cellular actions, rather than anti-A toxicity
alone, could be potential mechanisms underlying their in vivo effects.
In this proposed SBIR Phase II project, our original Phase I investigative team with additional expertise in rodent
brain imaging, clinical Alzheimer’s disease treatments, and non-GLP toxicity study providers, will conduct
longitudinal studies of pharmacokinetics and pharmacodynamics (PK/PD) on the two aforementioned TP
molecules in a new transgenic rat model of Alzheimer’s disease, in order to select the best lead as the IND
candidate. We now choose the new TgF344-AD rat model for our studies because they exhibit accumulation of
oligomeric A, Aplaque formation, Tau pathology, behavioral Impairment, and neuronal loss that faithfully
recapitulate hallmarks of human Alzheimer’s disease. We will achieve our goal by accomplishing the following
Specific Aims:
1. Conduct PK/PD studies of CP2 and TP70 on TgF344-AD rats using our established assays/tests.
The drug metabolism and PK studies include plasma and hepatocyte stability, plasma and brain protein
binding, plasma and CSF concentrations, metabolite identification, P450 inhibition/induction, and
excretion. In vivo efficacy especially cognition, brain imaging, and pathologic outcomes will be examined
along with Aβ and tau protein biomarkers in CSF and brain to correlate with PD outcomes.
2. Preparation for IND-enabling studies. Conduct pilot safety pharmacology and non-GLP toxicology on
the selected therapeutic candidates through contract service organizations to help make a go/no-go
decision for IND-enabling studies in a Competing Renewal of SBIR Phase IIB or other programs.
3. Explore mechanisms of action underlying CP2 and TP70 efficacy in the transgenic rat model of
Alzheimer disease. We will investigate CP2 and TP70 modulation of hippocampal synaptic, particularly
NMDA receptor-mediated synaptic activity, plasticity and extrasynaptic NMDA receptors-mediated
activity, and explore their links to other molecular and cellular actions
Success in Phase II will lead to an IND candidate. Once an IND application is filed, it will attract
non-government support and pharmaceutical partners for clinical development of this novel drug candidate
for the treatment of Alzheimer’s disease.
