title: New cathepsin D inhibitor library utilizing hydroxyethyl isosteres with cyclic tertiary 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).
authors: Department of Chemistry, Western Illinois University, Macomb, IL 61455, USA. RM-McConnell@wiu.edu
authors: Rose M
authors: RM
authors: McConnell
authors: Kalyani
authors: K
authors: Inapudi
authors: Naveen
authors: N
authors: Kadasala
authors: Karthika
authors: K
authors: Yarlagadda
authors: Priya
authors: P
authors: Velusamy
authors: Matthew S
authors: MS
authors: McConnell
authors: Adam
authors: A
authors: Green
authors: Carol
authors: C
authors: Trana
authors: Kelley
authors: K
authors: Sayyar
authors: James S
authors: JS
authors: McConnell
mesh_terms: D000588:Amines / Q000737:chemistry* / Q000494:pharmacology*; D002402:Cathepsin D / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D008099:Liver / Q000201:enzymology; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000588:Amines; D011480:Protease Inhibitors; D054852:Small Molecule Libraries; D002402:Cathepsin D