The approach of prodrug and antedrug/soft drug is useful for resolving formulation, delivery, and toxicity limitations on problematic drugs. A prodrug is a pharmacologically inactive derivative of an active parent drug. The “ante drug” or “soft” drug have been designed to exert their desired effect locally but they are inactivated in the circulation to reduce unwanted systemic effects. Recently, both prodrug and antedrug/soft drug are becoming an integral part of the drug discovery paradigm. The metabolic consideration is most important in the design of prodrug and antedrug/soft drug. Since esterase is abundantly present in several tissues, most of prodrugs and antedrugs/soft drugs are metabolized by esterases and fully converted to their active and inactive metabolite. Prodrug aimed improvement of bioavailability of parent drug is activated by esterases in liver and intestine before entering systemic circulation, then enough high plasma concentration of parent drug results in an appropriate pharmacological effect. Antedrug/soft drug is mainly inactivated in blood and liver. Therefore, the design of prodrug and antedrug/soft drug hardly possible without understanding several esterases in intestine, liver and blood. This review introduces the example of prodrug and antedrug/soft drug and describes the important enzymes involved in prodrug activation and antedrug/soft drug inactivation notably with respect to substrate specificity, tissue distribution and species difference.

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Bombesin receptor subtype-3 (BRS-3), known as a promising target for anti-obesity, is expressed not only in the brain but also in the intestine. Merck's clinical candidate, which showed anti-obesity effects in rats and dogs also caused cardiovascular (CV) adverse effects, such as an increase of body temperature, heart rate and blood pressure in animals. Hence, lowering the exposure of the compound to the brain is expected to avoid CV effects. We designed a novel bicyclic diazepine from a structural similarity between our compounds and Merck's candidate, and reduced brain penetration by lowering lipophilicity. To identify potent compounds without any CV effects on the central nerve system, a labile carboxylic ester with an antedrug functionality was introduced. Consequently, an antedrug, 5c, showed significant in vivo efficacy and no clear CV effect in dog iv infusion. Our study has paved the way for development of anti-obesity drugs with a safer profile.

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High-energy ionizing radiation is among the potential external triggers for precise control of the function and drug efficacy in living organisms, because the radiation reaction for activation of biomaterials can be regulated spatially and temporally without any additives. Herein, we demonstrated a radiation-activated prodrugs, the activities of which can be blocked by chemical modification, while their intrinsic activities are recovered by X-irradiation. Our studies illustrated that azidomethyl, indolequinone and disulfide groups have favorable functionalities for caging molecules and materials. We applied the prodrug strategy to antitumor agents, nucleic acid medicine and drug-encapsulating nanocarriers.

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As sulfa drug was found as the urinary metabolite of Prontosil in past times, early prodrugs were often discovered by chance. The prodrugs later on, however, have been synthesized by chemically modifying the pharmacologically active substance, most frequently, with an intension of increased lipophilicity for an improved intestinal absorption and efficient enzymatic conversion to the active substance in the body. This could be achieved based on plenty of knowledge on the activating enzymes like esterases. In cases where the chemical structures of active metabolites or the mechanisms of metabolic activation are unknown, however, we cannot implement such strategies. The examples are the thienopyridine antiplatelet agents whose active metabolites have not been structurally clarified for long even though their clinical usefulness as the anti-platelet drugs has been well established in human studies. In this article, we describe the mechanisms for metabolic activation of thienopyridines and impact of the differenes in the activation mechanism on the clinical outcomes.

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The development of nucleic acid therapeutics has been of prime interest. However there are a lot of drawbacks to overcome for medical application. In this manuscript, we review the chemical approaches including chemical synthesis, protecting groups, modifications and conjugation with functional residues to overcome those problems of oligonucleotides and discuss future development of nucleic acid therapeutics.

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