New cathepsin D inhibitor library utilizing hydroxyethyl isosteres with cyclic tertiary amines.
2012
The design and synthesis of hydroxyethylamine isosteres as inhibitors of cathepsin D based on SAR data have
been accomplished. A library of 96 of these hydroxyethylamine isosteres are described and many have proven to be very
potent inhibitors of human cathepsin D activity as measured using a fluorometric assay technique, via peptide substrate
Ac-Glu-Glu(Edans)-Lys-Pro-Ile-Cys-Phe-Phe-Arg-Leu-Gly-Lys(Methyl Red)-Glu-NH2. Compounds showing strongest
inhibition of cathepsin D activity were those that contain a hydroxyethyl-N’-2- or N’-(4-chlorophenyl)piperazine moiety
(IC50 values range from 0.55 to 8.5 nM), with N’-(2-pyrimidyl)piperizine (IC50 values range from 0.5 to 21.6 nM), with NN’-
L-piperazinocolinamide (IC50 values range from 0.001 – 0.25 nM), or N-N’-L-piperazinocolin-N-methylamide (IC50
values range from 0.015 – 7.3 nM) .
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