Prodrugs are bioreversible derivatives of drug molecules that undergo an enzymatic and/or chemical transformation in vivo to release the active parent drug, which can then exert the desired pharmacological effect. In both drug discovery and development, prodrugs have become an established tool for improving physicochemical, biopharmaceutical or pharmacokinetic properties of pharmacologically active agents. About 5-7% of drugs approved worldwide can be classified as prodrugs, and the implementation of a prodrug approach in the early stages of drug discovery is a growing trend. To illustrate the applicability of the prodrug strategy, this article describes the most common functional groups that are amenable to prodrug design, and highlights examples of prodrugs that are either launched or are undergoing human trials.

Prodrugs: design and clinical applications

Glycoproteins, glycolipids, and glycophospholipids (glycoconjugates) are components of membranes. The oligosaccharide residue is responsible for intercellular recognition and interaction; it acts as a receptor for proteins, hormones, and viruses and governs immune reactions. These significant activities have stimulated interest in oligosaccharides and glycoconjugates. With their help it should be possible to clarify the molecular basis of these phenomena and to derive new principles of physiological activity. Major advances in the synthesis of oligosaccharides have been made by the use of the Koenigs-Knorr method, in which glycosyl halides in the presence of heavy-metal salts are employed to transfer the glycosyl group to nucleophiles. The disadvantages of this procedure have led to an intensive search for new methods. Such methods will be discussed in this article. Emphasis is placed on glycoside and saccharide formation by 1-O-alkylation, on the trichloroacetimidate method, and on activation through the formation of glycosylsulfonium salts and glycosyl fluorides.

New Methods for the Synthesis of Glycosides and Oligosaccharides—Are There Alternatives to the Koenigs‐Knorr Method? [New Synthetic Methods (56)]

Nasal drug delivery--possibilities, problems and solutions.

Anomeric-oxygen activation for glycoside synthesis: the trichloroacetimidate method.

The prodrug concept has been used to improve undesirable properties of drugs since the late 19th century, although it was only at the end of the 1950s that the actual term prodrug was introduced for the first time. Prodrugs are inactive, bioreversible derivatives of active drug molecules that must undergo an enzymatic and/or chemical transformation in vivo to release the active parent drug, which can then elicit its desired pharmacological effect in the body. In most cases, prodrugs are simple chemical derivatives that are only one or two chemical or enzymatic steps away from the active parent drug. However, some prodrugs lack an obvious carrier or promoiety but instead result from a molecular modification of the prodrug itself, which generates a new active compound. Numerous prodrugs designed to overcome formulation, delivery, and toxicity barriers to drug utilization have reached the market. In fact, approximately 20% of all small molecular drugs approved during the period 2000 to 2008 were prodrugs. Although the development of a prodrug can be very challenging, the prodrug approach represents a feasible way to improve the erratic properties of investigational drugs or drugs already on the market. This review introduces in depth the rationale behind the use of the prodrug approach from past to present, and also considers the possible problems that can arise from inadequate activation of prodrugs.

Prodrugs—from Serendipity to Rational Design

Prodrug Approaches to Enhancement of Physicochemical Properties of Drugs IV: Novel Epinephrine Prodrug

Hydrolysis of leucine enkephalin in the nasal cavity of the rat — A possible factor in the low bioavailability of nasally administered peptides

Synthesis of 1-O-(2′-Acetoxy) benzoyl-α-D-2-deoxyglucopyranose, a Novel Aspirin Prodrug

Kinetics and mechanism of hydrolysis of 1‐(2′‐acetoxybenzoyl)‐2‐deoxy‐α‐D‐glucopyranose, a novel aspirin prodrug

A novel ester of the formula: AND THE NON-TOXIC PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF. The compound evidences increased stability and lipoidal solubility and is extremely valuable in the treatment of conditions responsive to sympathomimetic agents and especially the management of bronchial asthma.

James E Truelove

Papers

Prodrug Approaches to Enhancement of Physicochemical Properties of Drugs IV: Novel Epinephrine Prodrug

Hydrolysis of leucine enkephalin in the nasal cavity of the rat — A possible factor in the low bioavailability of nasally administered peptides

Synthesis of 1-O-(2′-Acetoxy) benzoyl-α-D-2-deoxyglucopyranose, a Novel Aspirin Prodrug

Kinetics and mechanism of hydrolysis of 1‐(2′‐acetoxybenzoyl)‐2‐deoxy‐α‐D‐glucopyranose, a novel aspirin prodrug

Ester of 3,4-dihydroxy-alpha (isopropylamino) methyl benzyl alcohol, composition and anti-asthma use thereof