Current Topics in Medicinal Chemistry - Volume 11, Issue 18, 2011

Nowadays, prodrugs are widely exploited in the pharmaceutical industry to obtain new and more effective therapeutic strategies at the lowest costs. In commenting about the success of this pharmaceutical innovation, it is enough to say that the currently commercialized prodrugs are definitely comparable to new synthetic drugs in terms of both their pharmacodynamic and pharmokinetic profiles. Accordingly, this approach does deserve further development in an effort to ameliorate the efficacy of the already exploited strategies. Nonetheless, despite the encouraging results obtained so far, the mainstream pharmaceutical industry still seems to express a note of skepticism about its effectiveness. Thus, in an attempt to dismantle any possible bias accruing against the prodrug strategy, this issue will take a look at the chemical classification, synthetic schemes, pharmacological efficacy, and pharmacokinetic improvements that characterize the novelty of this field. For decades the principal concern of pharmaceutical chemistry has been to design a broad range of new synthetic analogues structurally related to an active lead compound, causing, in the process, an unnecessary waste of time and economic resources. On the other hand, prodrugs, being bioreversible derivatives of active drugs, are much easier to synthesize, have a much higher probability of being active with fewer adverse effects, and, more important, entail far lower costs to synthesize. These reasons have thus generated considerable interest in the pharmaceutical industries committed to improving health by designing drugs at lower costs and in a shorter period of time without, though, having to undermine the therapeutic efficacy. Indeed, a burgeoning body of evidence has indicated that several prodrugs have already been successfully exploited in the treatment of several specific pathologies, including hypertension, colon diseases, cancer, hepatic and renal dysfunctions, disorders of the central nervous system, as well as viral infections. Thus, we hope that our readers by having the opportunity to glance at the whole issue, which indeed attempts to provide a comprehensive outlook of the chemical classification, the pharmacodynamic and pharmacokinetic profiles of these types of drugs, as well as their clinical application, will eventually acknowledge the need and the importance of developing and refining this new but undeniably promising pharmacological approach. Lastly, we are deeply grateful to our reviewers, who by taking part in the accomplishment of this issue, have also significantly contributed to the prodrug research.

The study of prodrugs that are chemically modified bioreversible derivatives of active drug compounds to alter their undesired properties has been expanded widely during the last decades. Despite the commercial success the prodrugs have afforded, the concept is still quite unknown among many scientist. Furthermore, many scientists regard prodrugs as a pure interest of academic research groups and not as a feasible solution to improve the delivery or targeting properties of new chemical entities, drug candidates failed in clinical trials, or drugs withdrawn from the market. Although there are still unmet needs that require addressing, prodrugs should be seen as fine-tuning tools for the successful drug research and development. This review represents the potential of prodrugs to improve the drug delivery by enhanced aqueous solubility or permeability as well as describes several targeted prodrug strategies.

D-galactose is a simple and natural compound that has mainly been exploited in prodrug strategies. Galactosyl prodrugs can be considered a good approach to reach different goals in clinical drug application, especially when traditional drugs are likely to fail therapeutically owing to reasons such as the lack of site specificity, toxicity, and chemical instability. Indeed, of paramount importance is their ability to increase the selectivity of the parent compound, a phenomenon that helps to reduce the incidence of adverse effects, while preserving intact the pharmacodynamic features of the parent drug. Study results have varied according to the type of linkage between the drug and the hydroxyl group exploited. By working with these parameters, researchers have been able not only to generate selective pharmacological targeting of brain, liver, and cancerous cells, but also to improve cellular permeability as well as the pharmacokinetic profile of parent drugs. This review describes the broad spectrum of possibilities for exploiting D-galactose as a vector for prodrug design and the synthetic strategies that allow its realization.

There is a great emphasis on research to discover methods aimed at enhancing the efficacy of drugs and reducing their toxicity and unwanted side effects. Prodrugs are biologically inactive compounds that are converted to actual drug molecule, through biotransformation, that combine with the receptors to produce the biological action. Prodrugs can thus be considered as drugs containing specialized nontoxic protective groups utilized in a transient manner to alter or eliminate the undesirable properties of the parent drug molecule. Hypertension is one of the leading risk factors for cardiovascular disease and represents a major health and economic burden. Most of the drugs for cardiovascular diseases have low oral bioavailability, short duration of action, first pass metabolism and variable lipohilicities. Out of the need to overcome these limitations, various prodrugs have been designed for antihypertensive agents. This review extensively focuses on various strategies used for design and development of prodrugs for the various classes of antihypertensives, emphasizing on the details regarding the need for prodrug synthesis for each class, structure, type of modification and goal achieved. It also provides an insight into the major advances in the field of antihypertensive prodrug research.

Earlier colon was considered as a black-box, acting as a site for production and temporary storage of excreta and responsible for absorption of electrolytes and water. But, with the discovery of sulfasalazine as colon-specific prodrug, the promising and challenging issue of treating local pathologies was presented with colon as an organ of significance for target-specific delivery of drugs. The need and desirable attributes of colon-specific drug delivery systems have been well recognized, extensively explored and documented in the literature. The success of a colon-specific prodrug depends on its rational design and understanding the demands of the organ to be targeted and the delivery system to be developed. The present review mainly focuses on anatomy/physiology of colon, colonic microbiota, enzymatic set up of colon, pathophysiology of local diseases of colon, factors, obstacles and rationale for designing colon specific drug delivery system, various targets, potential drug candidates and novel colon-targeting carriers along with varied linkages that could be explored, merits and demerits of this design and recent trends in this field. Brief review of methodologies for characterization and in vitro/in vivo release studies is presented. The available animal models with quantifying parameters for evaluating colon-targeting potential and effectiveness of the colon-specific prodrugs for inflammatory bowel disease is also included in this review.

Research in anticancer chemotherapy has produced outstanding results, and mean survival rates have significantly improved over the last ten years. Nevertheless, all approved drugs are still characterized by narrow therapeutic windows that result mainly from their high systemic toxicity combined with their marked lack of tumor selectivity. Medicinal chemistry responds to the resulting demands with new analogues of a lead drug, or by developing prodrugs. Prodrugs are inactive compounds, which are metabolized in the body, either chemically or enzymatically, in a controlled or predictable manner, to the active parent drug. This review describes the results of strategies in prodrug development, subdivided into the principal categories of anticancer agents. The chemical implementation of prodrug approaches is illustrated through selected drug candidates.

In the last twenty years a depth study on potential pharmaceutical applications of synthetic polymers at proteinlike structure as carrier for macromolecular prodrug production has been performed in academia and in industry. In particular α,β-poly(N-2-hydroxyethyl)-DL-aspartamide (PHEA), α,β-polyaspartylhydrazide (PAHy), poly(glutamic acid) (PGA), poly(aspartic acid) (PAA) and polylysine (PLL) have been extensively studied in this field. In the present review, the use of PHEA, PAHy, PGA as starting materials to prepare macromolecular prodrugs is reported and drug delivery and targeting aspects have been considered.