A series of new prodrugs of daunorubicin and doxorubicin which are candidates for antibody-directed enzyme prodrug therapy (ADEPT) is reported. These compounds (25a,b,c and 32a,b,c) have been designed to generate cytotoxic drugs after activation with beta-glucuronidase. As expected, recovery of the active drug was observed after enzymatic cleavage by Escherichia coli beta-glucuronidase as well as by a fusion protein which has been obtained from human beta-glucuronidase and humanized CEA-specific binding region. The six prodrugs are highly stable and are more than 100-fold less cytotoxic than doxorubicin against murine L1210 cell lines. The ortho-substituted phenyl carbamates 25a,b,c are better substrates for beta-glucuronidase than the corresponding para-substituted analogues. After taking into account additional factors such as stability in plasma and kinetics of enzymatic cleavage, we selected the o-nitro prodrug 25c for clinical trials.

Immobility scores in the swimming test and brain concentrations of desipramine were determined in rats and mice following repeated injection of the antidepressant versus acute administration of either a behaviorally effective or ineffective dose of the drug. Five injections (IP) of desipramine (each injection being performed at the measured T1/2 of the drug in the brain) reduced immobility scores by 30%, whereas this regimen resulted in brain drug concentrations not different from those obtained after a single, behaviorally ineffective dose of desipramine. It is suggested that the enhanced "antidepressant" response such as that frequently observed in animals after repeated injection of imipramine-like drugs does not involve accumulation of the drug in the brain.

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