2 research outputs found
Optimization of Hydroxyethylamine Transition State Isosteres as Aspartic Protease Inhibitors by Exploiting Conformational Preferences
NMR conformational
analysis of a hydroxyethylamine peptide isostere
developed as an aspartic protease inhibitor shows that it is a flexible
architecture. Cyclization to form pyrrolidines, piperidines, or morpholines
results in a preorganization of the whole system in solution. The
resulting conformation is similar to the conformation of the inhibitor
in the active site of BACE-1. This entropic gain results in increased
affinity for the enzyme when compared with the acyclic system. For
morpholines <b>27</b> and <b>29</b>, the combination of
steric and electronic factors is exploited to orient substituents
toward S1, S1′, and S2′ pockets both in the solution
and in the bound states. These highly preorganized molecules proved
to be the most potent compounds of the series. Additionally, the morpholines,
unlike the pyrrolidine and piperidine analogues, have been found to
be brain penetrant BACE-1 inhibitors
Optimization of Hydroxyethylamine Transition State Isosteres as Aspartic Protease Inhibitors by Exploiting Conformational Preferences
NMR conformational
analysis of a hydroxyethylamine peptide isostere
developed as an aspartic protease inhibitor shows that it is a flexible
architecture. Cyclization to form pyrrolidines, piperidines, or morpholines
results in a preorganization of the whole system in solution. The
resulting conformation is similar to the conformation of the inhibitor
in the active site of BACE-1. This entropic gain results in increased
affinity for the enzyme when compared with the acyclic system. For
morpholines <b>27</b> and <b>29</b>, the combination of
steric and electronic factors is exploited to orient substituents
toward S1, S1′, and S2′ pockets both in the solution
and in the bound states. These highly preorganized molecules proved
to be the most potent compounds of the series. Additionally, the morpholines,
unlike the pyrrolidine and piperidine analogues, have been found to
be brain penetrant BACE-1 inhibitors