1. New cathepsin D inhibitor library utilizing hydroxyethyl isosteres with cyclic tertiary amines
- Author
-
Karthika Yarlagadda, Naveen Reddy Kadasala, Kalyani Inapudi, Rose M. McConnell, James S. McConnell, Matthew S. McConnell, Priya Velusamy, Carol Trana, Adam Green, and Kelley Sayyar
- Subjects
Cathepsin D activity ,Stereochemistry ,Cathepsin D ,Assay technique ,Article ,Peptide substrate ,Small Molecule Libraries ,Piperazine ,chemistry.chemical_compound ,Inhibitory Concentration 50 ,chemistry ,Liver ,Methyl red ,Drug Discovery ,EDANS ,Moiety ,Humans ,Protease Inhibitors ,Amines - Abstract
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-NH(2). Compounds showing strongest inhibition of cathepsin D activity were those that contain a hydroxyethyl-N'-2- or N'-(4-chlorophenyl)piperazine moiety (IC(50) values range from 0.55 to 8.5 nM), with N'-(2-pyrimidyl)piperizine (IC(50) values range from 0.5 to 21.6 nM), with N-N'- L-piperazinocolinamide (IC(50) values range from 0.001 - 0.25 nM), or N-N'-L-piperazinocolin-N-methylamide (IC(50) values range from 0.015 - 7.3 nM).
- Published
- 2011