Galactosylated Prodrugs: A Strategy to Improve the Profile of Nonsteroidal Anti-Inflammatory Drugs

Abstract

Carbohydrates are one of the most abundant and important classes of biomolecules. The variety in their structures makes them valuable carriers that can improve the pharmaceutical phase, pharmacokinetics and pharmacodynamics of well-known drugs. D-galactose is a simple, naturally occurring monosaccharide sugar that has been extensively studied for use as a carrier and has proven to be valuable in this role. With the aim of validating the galactose-prodrug approach, we have investigated the galactosylated prodrugs ibuprofen, ketoprofen, flurbiprofen and indomethacin, which we have named IbuGAL, OkyGAL, FluGAL and IndoGAL, respectively. Their physicochemical profiles in terms of lipophilicity, solubility and chemical stability have been evaluated at different physiological pH values, as have human serum stability and serum protein binding. Ex vivo intestinal permeation experiments were performed to provide preliminary insights into the oral bioavailability of the galactosylated prodrugs. Finally, their anti-inflammatory, analgesic and ulcerogenic activities were investigated in vivo in mice after oral treatment. The present results, taken together with those of previous studies, undoubtedly validate the galactosylated prodrug strategy as a problem-solving technique that can overcome the disadvantages of NSAIDs.

Galactose: A Versatile Vector Unveiling the Potentials in Drug Delivery, Diagnostics, and Theranostics

“…Importantly, galactos-6 ′ -yl ester prodrugs have demonstrated their utility in enhancing cell permeability and improving the pharmacokinetic properties of various drugs, thereby significantly reducing the occurrence of adverse effects while maintaining the efficacy of the parent drugs. In another study published by the same group in 2021, the pharmacological and toxicological profiles of these galactosylated prodrugs were reported to be superior to those of the parent drugs, with a significant reduction in ulcerogenicity [25].…”

“…In another study published by the same group in 2021, the pharmacological and toxicological profiles of these galactosylated prodrugs were reported to be superior to those of the parent drugs, with a significant reduction in ulcerogenicity [ 25 ].…”

Radiosynthesis and Early Evaluation of a Positron Emission Tomography Imaging Probe [18F]AGAL Targeting Alpha-Galactosidase A Enzyme for Fabry Disease

“…The microsomal stability results showed that the compound was minimally cleared % aGal A activity The AGAL molecule showed a LogD value of −0.43. The AGAL molecule has multiple hydroxyl groups contributing to lower lipophilicity, but because of its sugar-like structure it is expected to have improved solubility and cell permeability similar to [ 18 F]FDG and other galactosylated prodrugs [9,10].…”

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“…The majority of NSAID moieties are chemically made up of carboxylic functional groups, which may be one of the causes of mucosal membranes' direct injury. The ester, amides, amine, and anhydride derivatives completely mask the carboxylic groups and decrease the main direct effect of gastrointestinal (GI) ulceration and irritation [11]. Recently, Dana Ameen et al has been paying special attention to the diclofenac derivatives which exhibited no toxicity, and the preservation of stomach wall mucus may be the cause of gastroprotective effect [12].…”

“…Docking of Anthranilic acid derivatives (compounds[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] …”