Organic Pharmaceutical Chemistry: Prodrugs

History & Basic Concept
The prodrug concept was first proposed by Albert in 1958.
Albert and his co-workers described prodrugs as pharmacologically inactive chemical derivatives that could be used to alter the physicochemical properties of drugs, in a temporary manner, to increase their usefulness and/or to decrease associated toxicity.
This included both compounds that are designed to undergo a transformation to yield an active substance and those that were discovered by serendipity to do so.
These two situations were distinguished by Harper, who in 1959 introduced the term drug Iatentiation to refer to drugs that were specifically designed to require bioactivation.
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Another two terms hard drugs and soft drugs were also introduced Hard drugs are compounds that are designed to contain the structural characteristics necessary for pharmacological activity but in a form that is not susceptible to metabolic or chemical transformation. In this way, the production of any toxic metabolite is avoided, and there is increased efficiency of action. Since the drug is not inactivated by metabolism, it may be less readily eliminated. Soft drugs are active compounds that after exerting their desired pharmacological effect are designed to undergo metabolic inactivation to give a nontoxic product. Thus soft drugs are considered to be the opposite of prodrugs. Ideally, the prodrug is converted to the original drug as soon as the derivative reaches the site of action, followed by rapid elimination of the released derivatizing group without causing side effects in the process.
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