As prodrug

Benzodiazepines have a low risk for abuse in anxiety disorder patients without a history of alcohol or other substance abuse. Among the benzodiazepines there may be a spectrum of abuse liability, with drugs that serve as prodrugs for desmethyldiazepam (e.g., clorazepate), slow-onset agents (e.g., oxazepam), and partial agonists (e.g., abecarnil) having the least potential for abuse. However, there is no currently marketed benzodiazepine or related drug that is free of potential for abuse. 

F%. 4 Important nucleoside analogs that have undergone clinical trials for treatment of HC V. Both PSI-6130 (R7128) and R1479 were administered to humans as prodrugs... 

Alkoxyalkanoate esters have been used as prodrugs to improve the oral bioavailability of antiviral agents such as (+)-cyclaradine (carbocyclic arabino-furanosyl adenine) [41]. (+)-Cyclaradine has been shown to be effective against herpes simplex virus in tissue culture at noncytotoxic concentrations. Two prodrugs of (+)-cyclaradine, namely, (+)-cyclaradine-5 -methoxyacetate (CM) and (+)-cyclaradine-5,-ethoxypropionate (CE) (Fig. 2), may be promising candidates... 

AJ Repta. Short-chain alkyl esters of L-dopa as prodrugs for rectal absorption. Pharm Res 6(6) 501-505, 1989. 

C Kwon, HT Nagasawa, EG DeMastr, FN Shirota. Acyl, N-protected alpha-aminoacyl, and peptidyl derivatives as prodrug forms of the alcohol deterrent agent cyanamide. J Med Chem 29 1922-1929, 1986. 

OH Drummer, B Jarrott. Captopril disulfide conjugates may act as prodrugs Disposition of the disulfide dimer of captopril in the rat. Biochem Pharmacol 33(22) 3568-1571, 1984. 

The less polar methyl ester 2 as prodrug showed better results in vivo and inhibits both farnesylation of the Ras protein and growth of Ras-transformed cells, whilst proliferation of Raf- or Mos-transformed cells was not influenced. Growth of human pancreatic adenocarcinoma cells with mutated K-Ras, c-Myc and p53 genes was inhibited by application of 2. If the compound is administered over a period of 5 days to mice with implanted Ras-dependent tumors, tumor growth can be reduced by up to 66% compared to untreated mice, whereas application of the antitumor antibiotic doxorubicin only resulted in 33% reduction under the same conditions. It is particularly noteworthy that treatment with the /1-turn mimetic - in contrast to treatment with doxorubicin - was without any visible side effects, such as weight loss. 

The diazeniumdiolate anions react with electrophiles to produce stable covalent compounds (Fig. 3.9) [213, 216]. These compounds have the ability to act as prodrugs, releasing nitric oxide only when metabolically or enzymatically converted to the diazeniumdiolate anion [217-219]. Several compounds ofthis class have been synthesized by reaction of alkyl or aryl halides, sulfate esters, epoxides, etc. with the ionic diazeniumdiolates [220, 221]. 

The 3-formyl analogues of norfloxacin, pefloxacin and ciprofloxacin, (82a-c) have also been shown to function as prodrugs of their respective parent... 

It has been postulated that carboplatin and its analogs act as prodrugs, reacting with chloride in plasma to give cisplatin. However, the rate of aquation of carboplatin is too slow to account for its in vivo activity (half-life 11 days in water), and the reactions of carboplatin with phosphate, chloride, or water are slower than direct reactions... 

Some sulfatases (sulfuric ester hydrolases, EC 3.1.6) play a pharmacological role in the hydrolysis of sulfuric acid ester metabolites and the few such esters that are used as prodrugs. Arylsulfatase (sulfatase, arylsulfohydrolase,... 

The next example is 1,3-dibenzoylurea (4.222), a diacetylated linear urea. The hydrolysis kinetics and enzymatic cleavage of 1,3-dibenzoylurea together with various other /V-acylbenzamides were studied to assess the suitability of these compounds as prodrugs for the amido group [113]. At pH 7.4 and 37°, 1,3-dibenzoylurea was hydrolyzed quantitatively to benzoic acid and N-benzoylurea (4.223) with a tm value of 39 h. Since the hydrolysis of 1,3-di-benzoylurea was not catalyzed by human plasma, it was concluded that the acyclic diureide structure is not appropriate in prodrug design. 

A. H. Kahns, H. Bundgaard, A-Acyl Derivatives as Prodrug Forms of Amides Chemical Stability and Enzymatic Hydrolysis of Various A-Acyl and A-Alkoxylcarbonyl Amide Derivatives , Int. J. Pharmaceut. 1991, 71, 31-43. 

Variously N-substituted glycolamide esters (TV-substituted carbamoylmethyl esters) of carboxylic acids have been proposed as prodrugs of particular... 

Fig. 8.1. Hydrolytic pathways in the activation of glycolic acid esters as prodrugs of active carboxylic acids. Reaction a is the desirable, direct activation, whereas Reaction b must be seen as parasitic in view of the relative slowness of Reaction c.

Recent studies with quinoline-4-carboxylic acid angiotensin II receptor antagonists have confirmed the interest of (oxodioxolyl)methyl esters as prodrugs with improved oral bioavailability and efficacy in laboratory animals [79], Olmesartan, another angiotensin II receptor antagonist, has also been derivatized to a (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl carboxylate designated as olmesartan medoxomil [80], In this case, both human serum albumin and arylesterase (presumably EC 3.1.1.2, although paraoxonase cannot be excluded) were shown to be involved in hydrolysis. 

In summary, (oxodioxolyl)methyl esters of carboxylic acid drugs appear to be generally useful as prodrugs. However, more studies are needed to document the structure-metabolism relationships, the relative contribution of enzymatic vs. nonenzymatic reactions in their in vivo activation, the reasons of some failures, their toxic potential, and their pharmacokinetic behavior in humans. 

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