Cathepsin D, a lysosomal aspartic protease, has been suggested to play a role in the metastatic potential of several types of cancer A high activated cathepsin D level in breast tumor tissue has been associated with an increased incidence of relapse and metastasis. High levels of active cathepsin D have also been found in colon cancer, prostate cancer, uterine cancer, and ovarian cancer. Hydroxyethyl isosteres with cyclic tertiary amine have proven to be clinically useful as inhibitors of aspartyl proteases, such as cathepsin D and the HIV1 aspartyl protease. Also cathepsin D has recently been associated with the development of Alzheimer's disease. Specific proteinase inhibitors, useful in investigations of the mechanisms and pathways of intracellular protein degradation, could lead to the development of therapeutic agents for treatment of many types of carcinomas as well as Alzheimer's disease. The design and the synthesis of (hydroxyethyl)amine isostere inhibitors with the cyclic tertiary amines is described. The IC-50 and apparent Ki values for several cathepsin D inhibitors are reported.
McConnell, Rose M.; Godwin, Walter E.; Sayyer, Kelley; Trana, Carol; Green, Adam; McConnell, Matthew; Young, Ashley; Young, Lauren; and Hatfield, Susan E.
"Synthesis and Evaluation of New Cathepsin D Inhibitors,"
Journal of the Arkansas Academy of Science: Vol. 59
, Article 18.
Available at: http://scholarworks.uark.edu/jaas/vol59/iss1/18