It is estimated that 40% of active new chemical entities (NCEs) identified in combinatorial screening programs employed by many pharmaceutical companies are poorly water soluble, i.e., these compounds have an aqueous solubility less than 10 |M (5 |g/mL for a compound with a molecular weight of 500) (Lipinski, 2002, 2004). When these poorly soluble NCEs are further advanced in discovery and ultimately brought into development they are often plagued by incomplete absorption and low, erratic bioavailability. There are a limited number of options available to drug discovery scientists to enhance the solubility of a compound by conventional formulation approaches. These include the identification and selection of stable pharmaceutical salts (Stahl, 2003). However, salt formation requires an ionizable group and, therefore, this is not a viable option for neutral compounds or those with ionization constants that do not fall within the physiological range. Other common approaches are reducing solid particle size by micronization, such as milling or the formation of nanosuspensions (Müller et al., 2001), the use of complexation agents such as cyclodextrins (Rao and Stella, 2003), or the use of solubilizing excipients (Strickley, 2004). While these solubi-lization techniques often lead to significant improvement in systemic exposure when availability is solubility- or dissolution-rate limited, conventional formulation approaches are not always successful and an alternate strategy is required.

One effective strategy for overcoming the low aqueous solubility is to convert the water-insoluble parent drug into a soluble prodrug. Broad objectives of a prodrug design often include enhanced bioavailability, fewer side effects, and improved patient acceptance and compliance. In some cases, a solubility-enhancing prodrug can successfully achieve all these goals.

Oral prodrugs are often designed to overcome an absorption limitation or related problem of their parent drugs (Notari, 1981; Stella et al., 1985; Neau, 2000; Ettmayer et al., 2004), such as poor solubility and/or poor permeability. Prodrugs can increase absorption relative to their parent drugs via several mechanisms, including (a) targeting carrier-mediated transporters such as hPepT1 with e.g., valacyclovir, which has enhanced permeability and solubility compared to acyclovir (Bai et al., 1992; Smiley et al., 1996; Sinko and Balimane, 1998; Anand et al., 2004; Sun et al., 2004), or XP13512, a prodrug of gabapentin that targets a nutrient transporter (Cundy et al., 2004); (b) masking a polar/charged functional group that prevents a molecule from penetrating lipophilic membranes, e.g., adefovir dipivoxil, (Annaert et al., 2000; Niemi et al., 2000; Van Gelder et al., 2000) and ester prodrugs of carboxylic acids (Beaumont et al., 2003); (c) perturbing crystal lattice packing by decreasing hydrogen bonding, yielding to lower melting point parent drugs with enhanced solubility in simulated gastric fluids (Stella et al., 1998); and (d) improving dissolution rate and/or solubility of a lipophilic drug, such as amprenavir and buparvaquone (Fleisher et al., 1996; Furfine et al., 2004; Mäntylä et al., 2004a,b).

While there are many "oral" prodrugs (Stella, 2004), including lipophilic carboxylic ester prodrugs that overcome poor cellular permeability and result in low systemic exposure of the polar carboxylic acid parent drug (Testa and Mayer, 2001; Beaumont et al., 2003), relatively few examples of marketed water-soluble oral prodrugs have been described (Ettmayer et al., 2004). In addition to standard modification such as the addition of ionizable groups, e.g., phosphates, or covalently linking polar neutral molecules, e.g., polyethylenglycols, some novel prodrug activation approaches have been described recently (Hamada et al., 2003).

Prodrug activation can occur enzymatically or non-enzymatically, i.e., by chemical hydrolysis such as intramolecular cyclization-elimination (Tamamura et al., 1998; Matsumoto et al., 2000,2001; Sohma et al., 2003; Hamel et al., 2004) or by O^N intramolecular acyl migration reactions (Kiso et al., 1999a; Matsumoto et al., 2001; Hamada et al., 2002, 2003, 2004; Hayashi et al., 2003a; Skwarczynski et al., 2003; Sohma et al., 2003). There is current interest in non-enzymatic hydrolysis or intramolecular catalysis of prodrugs, presumably due to their advantage in reducing biological variability.

While a number of prodrug design strategies have proven therapeutically successful (Ettmayer et al., 2004; Stella, 2004), there are only a few examples in which solubility-enhancing prodrugs have been of demonstrable clinical utility. This chapter describes prodrug strategies that discovery scientists can pursue in cases where conventional approaches to enhance solubility have either failed or are impractical (Tong, 2000). Some of the more commonly used water-soluble prodrugs for oral delivery that will be discussed include a) phosphate ester prodrugs where the phosphate promoiety is often attached directly to a functional group of a NCE (e.g., a hydroxyl) or, less commonly, via a small spacer group (Kearney, 1990; Stella, 1996) and b) polyethyleneglycol-conjugated parent drugs using a labile linker or spacer.

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