Prodrugs Launched

Structures 19-21.

Paul Ehrlich, the 1908 Nobel Laureate, coined the term "magic bullet" to describe drugs or therapies that selectively acted at their site of action with minimal exposure to the rest of the body (Ehrlich, 1906, 1908). He appeared to be one of the first to talk about a "receptor" in molecular terms. In addition, he also studied the role of drug metabolism in activating drugs in his seminal work on arsenicals (see Albert, 1985). Effectively, Ehrlich's magic bullet concept and his work on arsenicals were the precursor to today's ADEPT and GDEPT and prodrugs in general.

What Have You Done For Me Recently?

Examples of very recent commercial successes include the antivirals Hepsera® (22), a prodrug of adefovir (23) used to treat hepatitis B, and Viread® (24), a prodrug of tenofovir (25) used to treat HIV infections. Both Hepsera® and Viread® were developed at Gilead Sciences. Gilead was also responsible for the development of the anti-influenza drug Tamiflu® (26) or oseltamivir, an ethyl ester prodrug. Roche Holding AG introduced another antiviral prodrug Valcycte™ (27) while Sankyo/Forest introduced Benicar® (28), an antihypertensive prodrug. Prodrugs 22, 24, 26, 27, and 28 all show superior oral bioavailability compared to their active forms. Pfizer introduced Dynastat® (29), or parecoxib sodium, a water-soluble injectable form of its new COX-2 inhibitor valdecoxib (30).

Pro Medical Drugs
Structures 22-25. Structures 26-28.

Another very recent approval is Lexiva® (31), or fosamprenavir, a water-soluble phosphate ester, calcium salt, of amprenavir (32), which is used in the treatment of HIV infections (Anon, 2003). Jointly developed by Vertex and GlaxoSmithKline, fosamprenavir offers interesting clinical and economic advantages over amprenavir (Agenerase®), the parent drug. Amprenavir has an aqueous solubility of only 0.04 mg/mL and is formulated for adult use in soft gelatin capsules (SGC) containing 150 mg of drug along with ¿-alpha tocopheryl

Structures 29-30.

Structures 31-32.

polyethylene glycol (TPGS), polyethylene glycol 400 (PEG 400), and propylene glycol for a final weight of about 1 g. Because the daily dose of amprenavir is 1,200 mg twice a day, this requires patients to take eight capsules twice daily, which is clearly inconvenient. Although amprenavir is well absorbed from this dosage form, patient convenience and compliance is a problem. The aqueous solubility of fosamprenavir is said to be >0.3 mg/mL; it is supplied as a tablet containing 700 mg of the prodrug, equivalent to 600 mg of amprenavir. Thus, dosing becomes more convenient at two tablets twice a day, and blood levels of amprenavir comparable to those from the less convenient amprenavir SGC formulation are seen. The greater drug loading in the tablet is possible because of the higher solubility of fosamprenavir. For those unfamiliar with the use of polar phosphate esters for oral dosing, reading the work of Heimbach et al. (2003) is suggested. Although phosphate esters should show poor permeation from the GIT, the presence of high alkaline phosphatase levels on the surface of the enterocytes (the cells lining the small intestines) allows bioconversion of fosamprenavir to amprenavir at the brush-border lining followed by sequential amprenavir absorption. The "coupling" of metabolism and absorption is used by the body for the absorption of molecules such as folic acid (Rosenberg, 1981). The application of this coupling concept to prodrugs has been summarized previously by Fleisher and co-workers (1985) and more recently confirmed by the work of Heimbach et al. (2003) as applied to a number of phosphate ester prodrugs.

Fosamprenavir, as a prodrug of amprenavir, offers an additional advantage over amprenavir; it has restarted the patent clock. Amprenavir was patented earlier (Tung et al., 1996), whereas the fosamprenavir patent was issued in 2002 (Hale et al., 2002). Thus, while the protection by the composition of matter patent for amprenavir would expire around 2013, protection of the fosamprenavir patent would continue to at least 2019. While the development of fosamprenavir as a prodrug of amprenavir was probably costly, introducing fosamprenavir and encouraging physicians to prescribe fosamprenavir in place of amprenavir prior to patent expiration of amprenavir, those additional costs should be recouped by the longer exclusivity. That is, the additional costs to develop fosamprenavir would presumably be leveraged against future gains created by the extended patent life. Similar advantages were seen when Parke-Davis/Warner-Lambert introduced fosphenytoin or Cerebyx® as a safer injectable form of sodium phenytoin (Stella, 1996c), thus recapturing a market position lost earlier when sodium phenytoin injectable became generic.

Many of the ACE inhibitor antihypertensive drugs in the recent past are prodrugs, the first one being enalapril (33), the ethyl ester enalaprilate also known as MK-422 (Ulm, 1983). Poor oral bioavailability of the active species due to poor GIT permeation was the need addressed by these prodrugs. Similar improvements after oral dosing were seen with various ester prodrugs of third generation, non-amino side chain cephalosporins such as cefuroxime when administered as cefuroxime axetil (34) (Dellamonica, 1994).

Fosphenytoin ImagesFosphenytoin

In 1996, Warner-Lambert, now part of Pfizer, launched Cerebyx® (35), or fosphenytoin, as a water-soluble, safer form of sodium phenytoin (36) for the treatment of seizures (Stella, 1996c). Unlike some of the examples above, fosphenytoin is a prodrug of an older off-patent established product. The advantages of fosphenytoin over sodium phenytoin were such that commercialization of the prodrug could be justified. A similar scenario could be painted for Procif®, or fosfluconazole (37) (Bentley et at., 2002), a water-soluble injectable phosphate prodrug of Pfizer's very successful antifungal agent fluconazole (38). Fosfluconazole was approved in October 2003 in Japan. A water-soluble prodrug of ravuconazole (Bristol-Myers Squibb/Eisai), referred to as BMS-379224 (39), is in early clinical trials (Ueda et at., 2003).

An interesting example of a recently approved drug not recognized as a prodrug is Velcade® (40), or bortezomib. The aqueous solubility of bortezomib is quite limited (0.6 mg/mL, observations in our laboratory), but the parenteral freeze-dried form consists of 3.5 mg of drug and 35 mg of mannitol, which is reconstituted with 3.5 mL of normal saline to 1 mg/mL just prior to injection. Bortezomib in the formulation is present as a boronic acid ester with the mannitol (41). On reconstitution, the solution shows a solubility of >1 mg/mL because 40 exists in equilibrium with bortezomib (see Scheme 5) and the excess mannitol (Plamondon et at., 2004). Further dilution results in complete dissociation, which is presumably what happens upon IV administration of the drug.

Freeze Dried Bortezamib
Bortezomib Mannitol Ester


Scheme 5. Scheme showing the proposed reaction of bortezomib (40) with mannitol to form a boronic acid ester with superior water solubility (Plamondon et al., 2002).


Scheme 5. Scheme showing the proposed reaction of bortezomib (40) with mannitol to form a boronic acid ester with superior water solubility (Plamondon et al., 2002).

Another set of drugs not always recognized as prodrugs are so-called "suicide" inhibitor molecules. These are prodrugs that are activated to reactive species at or near their site of action. Upon metabolic activation, the reactive intermediate chemically reacts with a critical receptor components inactivating the receptor. Consider the approved drug Plavix® (42), or clopidogrel bisulfate, a platelet-aggregation inhibitor. Only a small portion of clopidogrel, a methyl ester, is metabolized by a complex P450-dependent pathway to 43 (2-oxoclopidogrel) and then to a thiol 44 (Pereillo et al., 2002), the stereospecific active metabolite. Cleavage of the methyl ester of clopidogrel leads to the inactive corresponding carboxylic acid. 44 is thought by Savi et al. (2001) to form a disulfide bond with the P2Y12 ADP-receptor on platelets, thus preventing ADP binding, a critical step in the platelet aggregation pathway. Disulfide formation with 44 may also contribute to the CYP2B6 inhibition by clopidogrel (Richter et al., 2004). The metabolic pathway for clopidogrel is shown in Scheme 6.

Earlier examples of suicide inhibitors as potential drugs led Bey (1978) and his colleagues at Merrell Research in Strasbourg to suggest that these inhibitors should be considered prodrugs. He reproduced one of the best cartoons in science to describe these suicide or Kcat inhibitors (Scheme 7). Here the prodrug (hand grenade) binds to the enzyme active site (the receptor), undergoes a chemical/biochemical event (pulling the pin of the hand grenade), producing a reactive species (the actual active species), which then destroys the enzyme/receptor by reacting with an essential functionality at the site (BOOM). The cartoon can be attributed to Professor Robert Rando of Harvard, one of the earlier researchers in this field. Numerous prodrug examples were discussed in the review by Bey (1978), including p-fluro D-alanine (45), a suicide substrate

Cartoons Drug Absorption
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