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Concluded Synthesis


L-685,458: g-secretase Inhibitor

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L-685,458 (3) is a potent inhibitor of g-secretase (IC 50 = 17 nM) and is of potential therapeutic benefit in the treatment of Alzheimer’s disease and other neurological disorders. This compound was originally developed as an HIV protease inhibitor. It was found to be a poor inhibitor of HIV protease, but a potent inhibitor of g-secretase. L-685,458 is a novel inhibitor of AbPP-g-secretase activity, with a similar potency for inhibition of Ab(42) and Ab(40) peptides.
L-685,458 contains a hydroxyethylene dipeptide isostere that should serve as a transition state analogue mimic to direct the inhibitor to the active site of an aspartyl protease target. The observation that the inhibitory potency of L-685,458 is sensitive to the configuration of the hydroxylic carbon atom and the substrate analogue L-682,679 (2) is processed by g-secretase (IC 50 > 10000 nM) and binds to the enzyme much less tightly than L-685,458 provide strong evidence that L-685,458 is an active site directed transition state analogue inhibitor for an aspartyl protease. This supports the conclusion that g-secretase is an aspartyl protease and agrees with a previous study showing that other aspartyl protease transition state analogues inhibit g-secretase activity in cells.

  1. "Allyltrichlorostannane Additions to alpha-Aminoaldehydes. Application to the Total Synthesis of the Aspartyl Protease Inhibitors L-682,679, L684,414, L-685,434, and L-685,458". Dias, L.C.; Diaz, G.; Ferreira, A.A.; Meira, P.R.R.; Ferreira, E. Synthesis 2003, 4, 603-622.

  2. "Short Total Synthesis of Aspartyl Protease Inhibitors L-685,434, L-682,679 and L-685,458", Dias, L.C, Ferreira, A.A. and Diaz, Gaspar Synlett 2002, 1845-1849.



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