Salicylic acid prodrugs

Figure 2 Three examples of 5-amino salicylic acid prodrugs sulfasalazine (I), olsala-zine (II), and balsalazine (III).

The case of aspirin in Table 8.3 is of special interest. Indeed, its acetyl ester group is particularly labile to enzymatic and nonenzymatic hydrolysis (see Sect. 7.4), and the reaction is even faster when the carboxy group is neutralized by esterification. A true ester prodrug of acetylsalicylic acid must fulfill the condition that its hydrolysis liberates aspirin rather than a prodrug of salicylic acid. An investigation of several aspirin prodrugs confirmed the interest of carbamoylmethyl esters and showed the (ATV-diethylcarbamoyl)methyl ester (Table 8.3) to liberate the highest proportion (ca. 60%) of aspirin [37], In... 

Most published examples of prodrugs of relevance in the present context contain an a-amino acyl moiety. A number of reasons may explain this fact, such as the lack of toxicity of these natural compounds, the large differences in lipophilicity and other properties between amino acids, and the variability afforded by A-substituents. Interesting examples are provided by salicylic acid and metronidazole. Thus, the hydrolysis of tyrosine and methionine prodrugs of salicylic acid (8.104 and 8.105, respectively) was examined in rabbits after intraduodenal and intracecal administration [134], The former ester, but not the latter, was hydrolyzed in the mucosa of the small intestine. In addition, both prodrugs underwent marked hydrolysis by intestinal microflora. 

J. Nakamura, M. Kido, K. Nishida, H. Sasaki, Effect of Oral Pretreatment with Antibiotics on the Hydrolysis of Salicylic Acid-Tyrosine and Salicylic Acid-Methionine Prodrugs in Rabbit Intestinal Microorganisms , Chem. Pharm. Bull. 1992, 40, 2572-2575. 

Preparations from plant materials containing salicylate have been used to treat pain and fever (Stone, 1763) from ancient times into the nineteenth century, when synthetic salicylic acid was synthesized in Germany and used for the same purposes. Acetyl salicylate, aspirin, synthesized as a prodrug for salicylate, was introduced by Bayer in 1899 (Dreser, 1899) and is still widely used to treat pain, fever, and inflammation. In low doses aspirin is also used by many to reduce the incidence of heart attacks by an antithrombotic effect (Antiplatelet Trialists Collaboration, 1994). Eventually, other drugs with therapeutic effects similar to those of aspirin were introduced, including indomethacin, ibuprofen, and naproxen. These... 

Figure 2.1 Acetylsalicylic acid 1 (Aspirin , Bayer) is much more than a prodrug of salicylic acid. Its major contribution to biological activity comes from a unique mechanism of action the activated acetyl group is transferred to a serine hydroxyl group in the binding site of cyclooxygenase. Merbaphen 2 (Novasurol , Bayer) was the first example of an organomercurial diuretic some analogs with less severe side effects were the therapeutic standard from about 1920 to 1950.

Inoue, M., Morikawa, M., Tsuboi, M. and Sugiura, M. (1979) Studies of human intestinal esterase. IV. Application to the development of ester prodrugs of salicylic acid. Journal of Pharmacohio-Dynamics, 2, 229-236. 

Oliyai R, Arimilli MN, Jones RJ, Lee WA (2001) Pharmacokinetics of salicylate ester prodrugs of cyclic HPMPC in dogs. Nucleosides Nucleotides Nucleic Acids 20 1411—1414... 

Details are given of the preparation of new biodegradable polyurethanes containing azo-linked polymeric prodrugs of amino salicylic acid in the main chain. Polymers were characterised by FTIR and proton NMR. Hydrolysis measurements were carried out. The hydrolysis product was detected using UV spectroscopy. 30 refs. 

An attempt is made to synthesise a polymer that will act as a controlled delivery device in targeting specific areas, such as the colon, over an extended period of time. The polymers being synthesised, polyanhydride esters, are composed of alkyl chains linked by ester bonds to aromatic moieties, specifically salicylic acid - the active component of aspirin. With the medicinal properties attributed to salicyclic acid and the ease of metabolism, the incorporation of this compound into a polymer backbone yields a polymeric prodrug that may have potential in a variety of applications, in particular, inflammatory bowel disease. For these reasons, a synthetic scheme that yields the desired polyanhydride esters is designed. Characterisation of the polymers is performed and presented along with preliminary in vitro and possible... 

S. Kumar, and Y.S. Negi, Corn cob xylan-based nanoparticles Ester prodrug of 5-amino-salicylic acid for possible targeted delivery of drug, /. Pharm. Sci. Res., 4 (12), 1995-2003, 2012. 

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