Chemistry:Aleplasinin

Aleplasinin is an experimental drug belonging to the class of plasminogen activator inhibitors (PAI-1 inhibitors). It is being developed by the U.S. pharmaceutical company Wyeth for potential use in the treatment of Alzheimer's disease.

Mechanism of action

In Alzheimer's disease, senile plaques composed of misfolded beta-amyloid peptides accumulate within neurons, together with neurofibrils. This accumulation leads to necrosis of the nerve cells.

The beta-amyloid peptide activates the tissue-specific plasminogen activator tPA (tissue plasminogen activator), which in turn activates plasminogen, thereby inducing the formation of plasmin. Plasmin promotes the degradation of beta-amyloid.

tPA, however, is inhibited by the plasminogen activator inhibitor PAI-1. In Alzheimer's disease, this inhibitor exhibits markedly increased activity. Aleplasinin selectively inhibits PAI-1, thereby preventing the enzyme inhibition of tPA. As a result, the degradation of the beta-amyloid peptide is enhanced, preventing its aggregation with neurofibrils in nerve cells. This process helps to prevent neuronal necrosis.

Literatur

• J.S. Jacobsen et al., M.N. Pangalos: Enhanced clearance of Aβ in brain by sustaining the plasmin proteolysis cascade, in: Proceedings Natural Academy Sciences, 2008, 105, S. 8754–8759; doi:10.1073/pnas.0710823105
• American Medical Association: