Prodrugs are most often taken into consideration after identification of a pharmacological active lead compound or structure. Consequently, the first step in prodrug design is identification of functional groups such as hydroxyl, carboxyl, carbonyl, amide, NH-acidic, and/or amino groups in the active compound that are available for chemical derivatization. Second, potentially bioreversible derivatives such as esters, N-acyl, N-hydroxymethyl, or N-acyloxyalkyl derivatives, N-Mannich bases, enaminones, and lactones may be synthesized and subjected to further testing. To this end, the most important requirement for a prodrug is its ability to adequately regenerate the active drug in vivo. In addition to this, it must be chemically stable in the bulk form and together with common excipients used in drug formulation leading to an acceptable shelf-life and, finally, the toxicity of the promoiety and the prodrug itself must be acceptable.
The necessary conversion or activation of the prodrug in the body to the active drug molecule can take place by both enzymatic- and nonenzymatic-mediated reactions, which is discussed in the following text.
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