Water‐Soluble Nitric‐Oxide‐Releasing Acetylsalicylic Acid (ASA) Prodrugs

Abstract

SummaryA new series of water-soluble (R-benzoyloxy) methyl esters of aspirin bearing at the benzoyl ring both alkyl chains containing nitric oxide (NO)-releasing nitrooxy groups and solubilizing moieties, was synthesized, and the products evaluated as true aspirin pro-drugs. Most products are solid substances and all posses good water solubility. They are quite stable in acid solutions (pH=1) and less stable at physiological pH. In human serum they are immediately metabolized by esterases, producing a mixture of aspirin (ASA), salicylic acid (SA), and of the related NO-donor benzoic acids, with other minor products. Due to aspirin release, the pro-drugs are capable of inhibiting collagen-induced platelet aggregation of human platelet-rich plasma. The simple NO-donor benzoic acids 28 and 48, studied as representative models of the whole class of benzoic acids formed following metabolism of the prodrugs in serum, did not trigger antiaggregatory activity when tested at 300 µM concentration. Only 28 displays quite potent NO-dependent vasodilatatory action. For two selected pro-drugs, 38 and 49, in vivo gastrotoxicity and anti-inflammatory properties are also reported: their anti-inflammatory activities are similar to that of aspirin when tested in the carrageenan-induced paw edema assay in rats. The gastrotoxicity the two pro-drugs was lower than that of aspirin in a lesion model in rats.

Nonsteroidal Anti‐Inflammatory Therapy: A Journey Toward Safety

“…The anti‐inflammatory efficacy of several NO‐donating derivatives of diclofenac, flurbiprofen, ketoprofen, naproxen, mesalamine, aspirin, indomethacin, ibuprofen, tolfenamic acid, and celecoxib has been reported using various animal models of acute and chronic inflammation. For instance, naproxcinod (Table ) and P2026 (an NO‐releasing derivative of diclofenac) have shown potent anti‐inflammatory activity either in a carrageenan‐induced paw edema model or in an adjuvant‐induced arthritis model .…”

Recent Developments in Chimeric NSAIDs as Safer Anti‐Inflammatory Agents

“…The compound 8 was found to be the most potent antiaggregatory agent with IC 50 of 20 μM, whereas 9 exhibited highest vasodilatory effects with EC 50 of 0.017 μM. In an effort to improve the bioavailability, Rolando et al synthesized a novel series of water‐soluble (benzoyloxy)methyl esters of aspirin . All the synthesized derivatives possessed alkyl chains containing a NO‐releasing nitrooxy group and a solubility‐enhancing aminoacyloxy moiety attached to the benzoyl ring.…”

Gaseous Mediators as a Key Molecular Targets for the Development of Gastrointestinal-Safe Anti-Inflammatory Pharmacology

“…Based on these physiological and pharmacological properties of NO, a new class of NO-releasing NSAIDs (NO-NSAIDs) was developed by chemically binding a NO-releasing moiety with the parent drug ( Fiorucci et al, 2001 ). Importantly, NO-NSAIDs have been shown to exert anti-inflammatory and analgetic effects comparable or even greater to those provided by conventional NSAIDs with markedly lower GI toxicity ( Wallace et al, 1995 ; Wallace et al, 1999 ; Al-Swayeh et al, 2000 ; Kato et al, 2001 ; Fiorucci et al, 2003 ; Fiorucci et al, 2004 ; Rolando et al, 2013 ). The anti-inflammatory activity of NO-NSAIDs have been proved by adding the NO moiety to various derivatives including aspirin, naproxen, ketoprofen, flurbiprofen, ibuprofen, diclofenac, indomethacin, mesalamine, tolfenamic acid, or celecoxib ( Pereira-Leite et al, 2017 ).…”