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New Cathepsin D Inhibitor Library Utilizing Hydroxyethyl Isosteres with Cyclic Tertiary Amines

[ Vol. 8 , Issue. 6 ]


Rose M. McConnell, Kalyani Inapudi, Naveen Kadasala, Karthika Yarlagadda, Priya Velusamy, Matthew S. McConnell, Adam Green, Carol Trana, Kelley Sayyar and James S. McConnell   Pages 1146 - 1154 ( 9 )


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) .


Aspartyl protease, Cathepsin D, Inhibitors, Hydroxyethylamine, Piperazine, Pipecolinate, Piperazinocolinate


Department of Chemistry, One University Drive, Western Illinois University, Macomb IL 61455, USA.

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