Prodrugs acetals

Viprostol (81) also incorporates a hydroxy group moved to C-16 and protects this from facile metabolic oxidation by vinylation. It is a potent hypotensive and vasodilatory agent both orally and transdermally. The methyl ester moiety is rapidly hydrolyzed in skin and in the liver so it is essentially a prodrug. It is synthesized from protected E-iodo olefin 78 (compare with 75) by conversion to the mixed organocuprate and this added in a 1,4-sense to olefin 79 to produce protected intermediate 80. The synthesis of viprostol concludes by deblocking with acetic acid and then reesterification with diazomethane to give 81 [19]. 

Aryl esters of retinoids have also received some interest. The 4-(acet-amido)phenyl ester of (all- )-retinoic acid, for example, showed topical activity in various animal models but was ineffective for the local treatment of acne in patients [86]. This difference is probably due to the prodrug being readily hydrolyzed in mice skin homogenates but not in human skin preparations. 

Like in Chapt. 7, we begin the discussion with acetates, since acetic acid is the simplest nontoxic acyl group, formic acid being less innocuous. An informative study was carried out to compare the kinetics of hydrolysis of two types of corticosteroid esters, namely methyl steroid-21-oates (which are active per se) and acetyl steroid-21-ols (which are prodrugs), as exemplified by methyl prednisolonate (8.69) and prednisolone-21-acetate (8.70), respectively [89]. In the presence of rat liver microsomes, the rate of hydrolytic inactivation of methyl steroid-21-oates was much slower than the rate of hydrolytic activation of acetyl steroid-21-ols. Thus, while the Km values were ca. 0.1 -0.3 mM for all substrates, the acetic acid ester prodrugs and the methyl ester drugs had Vmax values of ca. 20 and 0.15 nmol min-1 mg-1, respectively. It can be postulated that the observed rates of hydrolysis were determined by the acyl moiety, in other words by the liberation of the carboxylic acid from the acyl-enzyme intermediate (see Chapt. 3). 

F. Hirayama, K. Minami, K. Uekama, In vitro Evaluation of Biphenylyl Acetic Acid-/3-cyclodextrin Conjugates as Colon-Targeting Prodrugs Drug Release Behaviour in Rat Biological Media , J. Pharm. Pharmacol. 1996, 48, 27-31. 

Hirayama, F., Minami, K., and Uekama, K., In-vitro evaluation of biphenylyl acetic acid-beta-cyclodextrin conjugates as colon-targeting prodrugs drug release behaviour in rat biological media, J. Pharm. Pharmacol., 48 27-31 (1996). 

Indomethacin (Indocin) is an acetic acid derivative related functionally to sulindac (Clinoril), a prodrug with a long half-life, and etodolac (Lodine). They are metabolized in the liver and excreted as metabolites in the... 

Nabumetone is the only nonacid NSAID in current use it is converted to the active acetic acid derivative in the body. It is given as a ketone prodrug that resembles naproxen in structure (Figure 36-1). Its half-life of more than 24 hours (Table 36-1) permits once-daily dosing, and the drug does not appear to undergo enterohepatic circulation. Renal impairment results in a doubling of its half-life and a 30% increase in the area under the curve. 

Cundy, K. C., Annamalai, T., Bu, L., et al. XP13512 [( )-l-([(a-isobutanoyloxyethoxy) carbonyl] aminomethyl)-1-cyclohexane acetic acid], a novel gabapentin prodrug II. Improved oral bioavailability, dose proportionality, and colonic absorption compared with gabapentin in rats and monkeys. J. Pharmacol. Exp. Ther. 311 324-333, 2004. 

Low-dose regimens frequently result in very low corticosteroid concentrations in body fluids (e.g., low pg/mL range in plasma). PK analysis that is often necessary to manage these therapies is hindered by the inadequate sensitivity by most established analytical methods. In addition, certain drug delivery strategies, such as inhalation or intraocular injection, result in systemic levels too low to be detected by current methods. Furthermore, administration of some corticosteroid prodrugs, such as these in the forms of acetates/propionate, often results in sustained, low concentrations in plasma. Therefore, a highly sensitive and selective analytical approach is necessary for cases in which sustained low concentration of corticosteroids may be present systemically or in tissues. 

In certain situations, the diffusion process occurs concurrently with a particular reaction in the membrane. For instance, when a prodrug (i.e., estradiol acetate) diffuses through the skin, an enzyme in the viable epidermis converts the prodrug to estradiol and acetate. A diester prodrug (i.e., PNU-82, 899) diffuses across a Caco-2 cell monolayer, which extensively metabolizes the diester to a monoester. 

Tojo et al investigated the transdermal diffusion and metabolism of estradiol acetate in skin, as shown in Figure 6.33. The prodrug (estradiol acetate) is metabolized to estradiol in the viable epidermis. The concentration of the prodrug in the donor compartment is maintained at the saturated level. Calculate the diffusion coefficient... 

This assay is used for the quantitative determination of benazepril and its active metabolite, benazeprilat, in human plasma by capillary gas chromatography-mass selective detection (Pommier et al. 2003). Benazepril hydrochloride, 3- [l-ethoxycarbonyl-3-phenyl-(lS)-propyl]amino -2,3,4,5-tetrahydro-2-oxo-l-(3S)-benzazepine-l-acetic acid hydrochloride, is a prodrug-type angiotensin-converting enzyme (ACE) inhibitor which, on absorption, is hydrolysed to a pharmacologically active metabolite, the dicarboxylic acid (benazeprilat). 

Compound 25 (Fig. 18.9), a prodrug of 9-P-D-arabinofuranosyl guanine (26), was developed for the potential treatment of leukemia. Compound 24 is poorly soluble in water and its synthesis by conventional techniques is difficult. An enzymatic demethoxylation process was developed using adenosine deaminase (Mahmoudian et al., 1999, 2001). Compound 25 was enzymatically prepared from 6-methoxyguanine (27) and ara-uracil (28) using uridine phosphorylase and purine nucleotide phosphorylase. Each protein was cloned and overexpressed in independent Escherichia coli strains. Fermentation conditions were optimized for production of both enzymes and a co-immobilized enzyme preparation was used in the biotransformation process at 200 g/L substrate input. Enzyme was recovered at the end of the reaction by filtration and reused in several cycles. A more water soluble 5 -acetate ester of compound 26 was subsequently prepared by an enzymatic acylation process using immobilized Candida antarctica lipase in 1,4-dioxane (100 g/L substrate) with vinyl acetate as the acyl donor (Krenitsky et al., 1992). 

Non-prodrug water-soluble paclitaxel analogs were also reported. Because their C-10 positions were covalently attached to secondary amines instead of acetate in paclitaxel, they cannot convert into paclitaxel under physiological conditions. 

Wrasidlo, W. Gaedicke, G. Guy, R. K. Renaud, J. Pitsinos, E. Nicolaou, K. C. Reisfeld, R. A. Lode, H. N. A novel 2 -(N-methylpyridinium acetate) prodrug of paclitaxel induces superior antitumor responses in preclinical cancer models. Bioconjugate Chem., 2002, 13 1093-1099. 

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