Prodrugs of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), More Than Meets the Eye: A Critical Review

Abstract

The design and the synthesis of prodrugs for nonsteroidal anti-inflammatory drugs (NSAIDs) have been given much attention by medicinal chemists, especially in the last decade. As a therapeutic group, NSAIDs are among the most widely used prescribed and over the counter (OTC) medications. The rich literature about potential NSAID prodrugs clearly shows a shift from alkyl, aryalkyl or aryl esters with the sole role of masking the carboxylic acid group, to more elaborate conjugates that contain carefully chosen groups to serve specific purposes, such as enhancement of water solubility and dissolution, nitric oxide release, hydrogen sulfide release, antioxidant activity, anticholinergic and acetylcholinesterase inhibitory (AChEI) activity and site-specific targeting and delivery. This review will focus on NSAID prodrugs that have been designed or were, later, found to possess intrinsic pharmacological activity as an intact chemical entity. Such intrinsic activity might augment the anti-inflammatory activity of the NSAID, reduce its side effects or transform the potential therapeutic use from classical anti-inflammatory action to something else. Reports discussed in this review will be those of NO-NSAIDs, anticholinergic and AChEI-NSAIDs, Phospho-NSAIDs and some miscellaneous agents. In most cases, this review will cover literature dealing with these NSAID prodrugs from the year 2006 and later. Older literature will be used when necessary, e.g., to explain the chemical and biological mechanisms of action.

Mechanisms, prevention and clinical implications of nonsteroidal anti-inflammatory drug-enteropathy

“…Pro-drugs have been defined as "bioreversible derivatives of drug molecules that undergo an enzymatic and/or chemical transformation in vivo to release the active parent drug, which can then exert the desired pharmacological effect" [128,129] . A number of NSAID pro-drugs have been developed, based on the premise that if the drug can pass through the stomach in an inactive form, it will not inhibit PG synthesis in the stomach, and therefore will not be ulcerogenic.…”

“…Several approaches have been taken that show promise, mainly using the "codrug" model of drug design [142] . Co-drugs are somewhat like pro-drugs, with the key difference being that the promoiety is not inert; rather, it exerts important pharmacological effects [129] . Two such classes of co-drugs are the nitric oxide (NO)-releasing NSAIDs and the hydrogen sulfide (H2S)-releasing NSAIDs [143][144][145] .…”

Medicinal Chemistry: Insights into the Development of Novel H2S Donors

“…However, the mechanisms of H 2 S release from this type of molecules are still unclear. H 2 S can be generated when heating DTTs to 120 C in a DMSO-phosphate buffer mixture (Scheme 3), indicating that DTTs may be considered as hydrolysis-based H 2 S donors (Qandil 2012). It was found that H 2 S release from DTTs is a result of metabolic events, and enzymes such as esterases may be involved ).…”

Fluorescence Recognition of H2S by a Benzothiazole Derivative and Its Live Cell Imaging

“…人体内硫化氢的含量 与阿尔兹海默氏症、唐氏综合症、糖尿病和肝硬化等疾 病也密切相关 [3] . 此外, 硫化氢能够作为体内的一种抗 氧化剂清除多种氧化性物质 [4] , 硫化氢也可以起到抑制 炎症与保护心血管的作用 [5] . 由此可见, 对硫化氢的检 [12] , 因此 NaHS 被广泛用作水溶 液中 H 2 S 的来源 [13] .…”