A drug that halted or significantly slows disease progression at the pre-dementia stage, when only mild cognitive impairment is evident, would be a huge breakthrough compared to current options.  There is a growing body of evidence that (i) increasing neuroprotection and (ii) reducing neuroinflammation will significantly delay AD onset and reduce AD progression. 

There is substantial evidence suggesting that neurosteroids exert a variety of effects that will have a positive effect on AD progression including: neuroprotection; neurogenesis; neuronal growth; neurotransmission; synaptogenesis; myelination; and glial and neuronal differentiation.  On the other hand, pro-inflammatory cytokines (e.g., IL-1b and IL-6), are pivotal to a vicious circle between microglia activation, pro-inflammatory cytokines production, Aβ deposition and tau accumulation, that ultimately result in neuronal loss.

The lead compound we identified increases the levels of (i) neurosteroids (e.g., pregnenolone and allopregnanolone), (ii) lowers levels of pro-inflammatory cytokines and (iii) has good drug-like properties for a CNS drug.  Our lead is a racemic compound (e.g., a mixture of two mirror image isomers called enantiomers), and it is likely that most of the bioactivity resides in one isomer, while the other one has no benefit.  Thus, we plan to separate the enantiomers and identify the active one.  Then, through medicinal chemistry and sophisticated cell-based assays, we will optimize new analogs of the active enantiomer with the goal of identifying compounds ready for pre-clinical testing in mouse models of AD.