Alzheimer's therapeutics: neurotrophin domain small molecule mimetics

Factors limiting the therapeutic application of neurotrophins to neurodegenerative diseases include poor stability and CNS penetration. Moreover, certain neurotrophin effects, such as promotion of neuronal death via interaction with the p75NTR receptor, might further limit their application. We have proposed that development of small molecule mimetics of neurotrophins might serve to overcome these limitations. In previous work, our laboratory established the proof-of-principle that mimetics of specific nerve growth factor (NGF) domains could prevent neuronal death. Peptidomimetics of the loop 1 domain prevent death via p75NTR-dependent signaling and peptidomimetics of the loop 4 domain prevent death via Trk-related signaling. In current work we are designing pharmacophore queries corresponding to loop domains 1 or 4 that incorporate features of the NGF crystal structure along with features derived from peptidomimetic structure-activity-relationships. Screening of in silico databases containing non-peptide, small molecules has identified a number of candidate NGF domain mimetics. Preliminary assessment of these compounds using neurotrophin bioassays indicates that several are capable of preventing neuronal death. Ongoing studies will determine whether these compounds act via p75NTR or Trk receptors.