What Have You Done for Me Recently

The prodrug concept has been the subject of numerous reviews by Harper, 1959, 1962; Sinkula and Yalkowsky, 1975; Higuchi and Stella, 1975; Sinkula, 1975; Roche, 1977; Bundgaard, 1985; Bundgaard, 1989; Sloan, 1992; Stella, 1996a; Wermuth, 1996. All tell an eloquent tale of the prodrug story while Denny, 2001, 2003; Seddon et al., 2004; and others too numerous to mention discuss how the technique has specific targeting applications in areas such as cancer chemotherapy. The prodrug technique clearly has utility. Of the 43 new drugs approved in 1993, five were prodrugs and an additional two or three had structures indicating the possibility that they might have active metabolites (Stella, 1996b). Bernardelli et al. (2002) and Doherty (2003) reported on new approved drugs for 2001 and 2002. In that two-year period there were 49 new chemical entities (non-biologicals) approved, seven, or 14%, of which were clearly prodrugs, one was an acknowledged "soft" drug and one could argue that three other approvals were possibly acting as prodrugs. Table I provides the structures of some of these recently approved prodrugs, the barrier that was overcome and the enzymatic/chemical process likely for the bioreversion of the prodrug to drug. The most well known examples in this table are ones used to overcome GIT permeability and solubility limitations. Also included are a few examples that were approved a few years earlier, as well as an example of a prodrug that is currently in later phase clinical trials. This list is not comprehensive but does illustrate some very successful newer examples.

Some colleagues and I are currently completing an extensive new book on prodrugs to be titled "Prodrugs: Challenges and Rewards" that should be published in 2006 by Springer. Included in the book will be numerous case study chapters that will highlight both old and new examples of commercially successful prodrugs.

The patent literature also provides some insight into the future, since drugs will only be developed if their exclusivity can be protected. The patent literature on prodrugs has recently been reviewed (Stella, 2004). Although the search engine used was not comprehensive (Stella, 2004), the trends were notable. That is, there was an almost exponential increase in prodrug patents over the 10-year period. Many of these patents were described as being defensive patents. Just as in the past when terms such as "and physiologically acceptable salts thereof" began to be used to cover possible future novel salts from competitors, statements such as "and prodrugs thereof" have begun to appear. This was most prevalent in patents originating from Japan but has also begun to appear in patents from American-based multinationals (see Stella, 2004 for a more complete discussion of

Prodrug clinical use

Structure

Mechanism

latanoprost (Xalatan) glaucoma

"S ^ ______

corneal permeability, tolerance, safety

esterases byproduct is isopropyl alcohol

travoprost (Travatan) glaucoma

OH

corneal permeability, tolerance, safety

esterases byproduct is isopropyl alcohol

unoprostone isopropyl (Rescula) glaucoma

corneal permeability, tolerance, safety

esterases byproduct is isopropyl alcohol

bimatoprost (Lumigan) open-angle glaucoma

corneal permeability, tolerance, safety

amidases byproduct is ethylamine

tenofovir disoproxil fumarate (Viread) antiviral used to treat AIDs

'oh. 0

GI permeability

esterases and phosphodiestereases byproducts are carbon dioxide, isopropyl alcohol, formaldehyde

adefovir dipivoxil (Hepsera) hepatitis B antiviral

0

GI permeability

esterases and phosphodiestereases byproducts are pivalic acid formaldehyde

valacyclovir hydrochloride (Valtrex) antiviral

HCl NH2

0 CH.

GI permeability

esterases/ peptidases byproduct is L-valine

valganciclovir hydrochloride (Valcyte) antiviral

HCl "H2

H0^ 0 "

GI permeability

esterases/ peptidases byproduct is L-valine

oseltamivir (Tamiflu) anti-influenza (neurominidase inhibitor)

HC0CHN

ft .H2P0. NH2

GI permeability

esterases byproduct is ethanol

Table 1. (Continued on next page.)

Prodrug clinical use

Structure

Mechanism

olmesartan medoxomil (Benicar) anti-hypertensive

H,C. OH H,C' N CH, you (nA

GI permeability

esterases byproducts are carbon dioxide and 2,3 butanedione

ximelagatran

(Exanta) anticoagulant clot preventive

GI permeability

esterases, and reductive enzymes byproducts ethanol other products

prulifloxicin (Sword, Japan) antibacterial

O-OCC^^

presumed to be improved oral bioavailability

paraoxonase byproducts are carbon dioxide and 2,3 butanedione

fosamprenavir

(Lexiva) HIV protease inhibitor antiviral

Ca┬╗ ^^

ease of formulation for oral dosing patient compliance

phosphatases byproduct is inorganic phosphate

fs

phosphatases

fosphenytoin

(Cerebyx) anticonvulsant

Alf0 0 n 0

II Na+ O

greater safety, ease of administration

byproducts are formaldehyde and inorganic phosphate

fosfluconazole (Procif, Japan) antifungal

(UOH

F

adequate solubility for parenteral dosing

phosphatases byproduct is inorganic phosphate

aquavan (in phase III clinical trials) anesthetic

Na.

solubility and lower pain on injection aqueous versus emulsion formulation

phosphatases byproducts is inorganic phosphate and formaldehyde

parecoxib sodium (Dynastat) analgesic

-----m

adequate solubility for parenteral dosing

unknown but presumably esterases/

peptidases/

amidases byproduct is proprionic acid

Table 1. Table showing the structures and properties of some prodrugs approved by various regulatory bodies since 1996. This list is not comprehensive.

Table 1. Table showing the structures and properties of some prodrugs approved by various regulatory bodies since 1996. This list is not comprehensive.

this topic). A separate search at the US Patent Office site for the period 1976 to the present using just the word prodrug/s resulted in about 6,500 hits. This probably underestimates the real number by at least 50% as many prodrugs are not identified as such. Similar searches in PubMed and SciFinder with the keyword prodrug/s resulted in high publication hit rates confirming the patent trend.

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