Development of cathepsin D inhibitors with new hydroxyethyl piperazine derivatives

Abstract

Cathepsin D, a lysosomal aspartic protease, clearly plays a role in the tumor processes and metastasis of several types of cancer. An increased incidence of relapse and metastasis of breast cancer has been assocd. with a high activated serum cathepsin D level. High levels of active cathepsin D have also been found in patients with uterine, ovarian, colon, and prostate cancers. In addn., cathepsin D may be implicated in Alzheimer's disease. Polymorphism of the cathepsin D gene has been isolated in patients diagnosed with Alzheimer's. Aspartyl proteases with substrate specificity similar to cathepsin D, such as the HIV-1 aspartyl protease, have demonstrated inhibition with the clin. use of hydroxyethyl isosteres with piperazine derivs. (cyclic tertiary amines). The design and the development of twelve new hydroxyethyl isostere inhibitors with piperazine derivs. is described, using Hb as the substrate. The IC50 values and K1 (apparent) for these cathepsin D inhibitors are now reported. [on SciFinder (R)]