Second-Generation Aspirin and Indomethacin Prodrugs Possessing anO²-(Acetoxymethyl)-1-(2-carboxypyrrolidin-1-yl)diazenium-1,2-diolate Nitric Oxide Donor Moiety: Design, Synthesis, Biological Evaluation, and Nitric Oxide Release Studies

Abstract

The carboxylic acid group of the anti-inflammatory (AI) drugs aspirin and indomethacin was covalently linked to the 1-(2-carboxypyrrolidin-1-yl)diazen-1-ium-1,2-diolate ion via a one-carbon methylene spacer to obtain two new hybrid prodrugs. The aspirin prodrug ( 23) was a 2.2-fold more potent AI agent than aspirin, whereas the indomethacin prodrug ( 26) was about 1.6-fold less potent than indomethacin. Prodrugs 23 and 26 slowly released nitric oxide (NO) upon dissolution in phosphate buffer at pH 7.4 (1.1 mol of NO/mol of compound after 43 h), but the rate and the extent of NO release were higher (1.9 mol of NO/mol of compound in 3 min or less) when the compounds were incubated in the presence of porcine liver esterase. In vivo ulcer index (UI) studies showed that the aspirin prodrug 23 (UI = 0.7) and indomethacin prodrug 26 (UI = 0) were substantially less ulcerogenic than the parent drugs aspirin (UI = 51) and indomethacin (UI = 64).

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Progress in Small Molecule Drug Development

“…In another follow-up study, the indomethacin derivative linked to a 1-(2-carboxypyrrolidin-1-yl)diazen-1-ium-1,2-diolate by a methylene spacer ( 7 ) exhibited oral anti-inflammatory activity while exhibiting no GI toxicity (0.08 mmol/kg, oral dose). The in vitro assay data showed that these NO-donating prodrugs were devoid of COX inhibition [30,31]. …”

Anti-inflammatory properties of Dirinaria consimilis extracts in albino rats

“…[2,3] The chronic inflammations may lead to various diseases such as cancer [4], atherosclerosis [5], Alzheimer's [6] and rheumatoid arthritis. [7] Historically, Willow bark extracts were used to treat the fever, inflammation and pain, thereafter the non-steroidal anti-inflammatory drugs (NSAIDs) which include organic acids and non-acidic compounds and coxibs (celecoxib, rofecoxib, etc) were drugs of choice to treat inflammation. [7,8] In contrast, these synthetic drugs were noticed to have adverse effects on cardiac, gastrointestinal, renal, and vascular functions.…”

“…[7] Historically, Willow bark extracts were used to treat the fever, inflammation and pain, thereafter the non-steroidal anti-inflammatory drugs (NSAIDs) which include organic acids and non-acidic compounds and coxibs (celecoxib, rofecoxib, etc) were drugs of choice to treat inflammation. [7,8] In contrast, these synthetic drugs were noticed to have adverse effects on cardiac, gastrointestinal, renal, and vascular functions. [8] Therefore, keeping in mind of the aforementioned drawbacks, the evolution of novel anti-inflammatory agents having lesser adverse effects are highly desirable.…”

Effects of nitric oxide-releasing nonsteroidal anti-inflammatory drugs (NONO-NSAIDs) on melanoma cell adhesion

“…Long-term use of NSAIDs can cause side-effects such as cardiovascular and gastrointestinal injuries (Lichtenberger et al , 2006; Ng and Chan, 2010). A new class of nitric oxide (NO•)-releasing NSAIDs possessing a N -diazen-1-ium-1,2-diolate moiety (NONO-NSAIDs) were recently developed and have shown a reduction of harmful side-effects in comparison with normal NSAIDs (Velazquez et al , 2005a; Velazquez et al , 2007; Velazquez et al , 2008; Abdellatif et al , 2009; Chattopadhyay et al , 2010). In addition to their anti-inflammatory profile, NONO-NSAIDs have shown potential for usage in cancer prevention and treatment (Chattopadhyay et al , 2010; Flores-Santana et al , 2012).…”