Novel ibuprofen prodrugs with improved pharmacokinetics and non-ulcerogenic potential

In the present study, we evaluated the anti-inflammatory activity with pharmacokinetic, ulcerogenic properties of various synthesized prodrugs of ibuprofen in experimental animals. Prodrugs 2, 6, 9, 10, 12, and 14 were found to possess significant anti-inflammatory activity with almost non-ulcerogenic potential than standard drug ibuprofen 1a in both normal and inflammation-induced rats. Metabolic stability of prodrugs 2, 6, 9, 10, 12, and 14 were also studied in rat liver microsomes and oral bioavailability was determined by estimating area under curve (AUC) and plasma concentration of these prodrugs at various time intervals. The experimental findings elicited higher AUC and plasma concentration at 1 and 2 h indicating improved oral bioavailability as compared to parent ibuprofen. These prodrugs are found to have least gastric ulceration with retain anti-inflammatory activity observed in experimental animals. Therefore, present experimental findings demonstrated significant improvement of various pharmacokinetic properties with least ulcerogenic potential of ester prodrugs of ibuprofen an anti-inflammatory agent     

Synthesis of Novel Substituted Thiourea and Benzimidazole Derivatives Containing a Pyrazolone Ring as Anti‐Inflammatory Agents

Two series of new 1‐(alkyl/aryl)‐3‐{2‐[(5‐oxo‐4,5‐dihydro‐1H‐pyrazol‐3‐yl)amino]phenyl}thioureas 2a – h and 5‐[2‐(substituted amino)‐1H‐benzimidazol‐1‐yl]‐4H‐pyrazol‐3‐ols 3a – i were designed and synthesized as anti‐inflammatory agents. The cyclooxygenase inhibitory activity of the newly synthesized compounds was investigated. All the compounds showed non‐selective inhibition of COX‐1 and COX‐2 enzymes which was consistent with their docking results. Compounds 2c , 2f , 2g , 3b , and 3g that showed the highest COX‐2 inhibitory activity were selected for further in vivo testing as anti‐inflammatory agents using diclofenac as a reference drug. Two of the test compounds ( 2c and 3b ) showed potent anti‐inflammatory activity comparable to that of diclofenac with lower ulcerogenic effect relative to indomethacin. SAR study of the two series as cyclooxygenase inhibitors and anti‐inflammatory agents was also provided.     

Synthesis,molecular docking,and pharmacological evaluation of N‐(2‐(3,5‐dimethoxyphenyl)benzoxazole‐5‐yl)benzamide derivatives as selective COX‐2 inhibitors and anti‐inflammatory agents

A series of N‐(2‐(3,5‐dimethoxyphenyl)benzoxazole‐5‐yl)benzamide derivatives ( 3am ) was synthesized and evaluated for their in vitro inhibitory activity against COX‐1 and COX‐2. The compounds with considerable in vitro activity (IC₅₀ < 1 μM) were evaluated in vivo for their anti‐inflammatory potential by the carrageenan‐induced rat paw edema method. Out of 13 newly synthesized compounds, 3a , 3b , 3d , 3g , 3j , and 3k were found to be the most potent COX‐2 inhibitors in the in vitro enzymatic assay, with IC₅₀ values in the range of 0.06–0.71 μM. The in vivo anti‐inflammatory activity of these six compounds ( 3a , 3b , 3d , 3g , 3j , and 3k ) was assessed by the carrageenan‐induced rat paw edema method. Compounds 3d (84.09%), 3g (79.54%), and 3a (70.45%) demonstrated significant anti‐inflammatory activity compared to the standard drug ibuprofen (65.90%) and were also found to be safer than ibuprofen, by ulcerogenic studies. A docking study was done using the crystal structure of human COX‐2, to understand the binding mechanism of these inhibitors to the active site of COX‐2.

     

Evaluation of Anti‐inflammatory and Analgesic Effects of Synthesized Derivatives of Ibuprofen

Inflammatory and pain are major areas for drug discovery. Current analgesic drugs often cause a number of side‐effects. In the present study, we modified carboxylic acid group of ibuprofen, one of non‐steroidal anti‐inflammatory drugs, based on the common structure of transient receptor potential vanilloid type 1 antagonists which are considered as new candidates for analgesic drugs, and synthesized several derivatives of ibuprofen. Comprehensive evaluations of the pharmacological properties of these compounds were investigated. Compound 17 showed weak cyclooxygenase inhibition and exhibited strong transient receptor potential vanilloid type 1 antagonistic activity. It was found to be capable of blocking noxious thermal nociception and capsaicin‐induced nociception in mice. Besides, 17 showed less ulcerogenic action than ibuprofen did and had no hyperthermia side‐effect compared with common transient receptor potential vanilloid type 1 antagonists. Therefore, it suggested that 17 could be used as a safe alternative analgesic candidate for pain treatment.     

Evaluation of anti-inflammatory, anti-nociceptive, and anti-ulcerogenic activities of novel synthesized thiazolyl and pyrrolyl steroids

Developing new therapeutic agents that can overcome gastrointestinal injury and at the same time could lead to an enhanced anti‐inflammatory effect becomes an urgent need for inflammation patients. Thiazolyl and pyrrolyl steroids were synthesized via straight forward and efficient methods and their structures were established based on their correct elemental analysis and compatible IR, ¹H‐NMR, ¹³C‐NMR, and mass spectral data. The dihydrothiazolyl‐hydrazonoprogesterone 12 and the aminopyrrolylprogesterone 16a showed anti‐inflammatory, antinociceptive, and anti‐ulcerogenic activity with various intensities. Edema were significantly reduced by both doses of tested compounds (25 and 50 mg/kg) at 2, 3, and 4 h post‐carrageenan. The high dose of compound 16a was the most effective in alleviating thermal pain. Gastric mucosal lesions, caused in the rats by the administration of ethanol or indomethacin (IND), were significantly inhibited by each of the two tested compounds. These results provide a unique opportunity to develop new anti‐inflammatory drugs which devoid the ulcerogenic liabilities associated with currently marketed drugs.     

Synthesis,Molecular Docking,and Biological Evaluation of Some Novel Hydrazones and Pyrazole Derivatives as Anti‐inflammatory Agents

2‐Hydrazinyl‐N‐(4‐sulfamoylphenyl)acetamide 3 was the key intermediate for the synthesis of novel hydrazones 4–10 and pyrazole derivatives 11–17 . All compounds were tested for their in vivo anti‐inflammatory activity and their ability to inhibit the production of PGE₂ in serum samples of rats. IC₅₀ values for the most active compounds for inhibition of COX‐1 and COX‐2 enzymes were determined in vitro, and they were also tested for their ulcerogenic effect. Molecular docking was performed on the active site of COX‐2 to predict their mode of binding to the amino acids. Most of the synthesized compounds showed good anti‐inflammatory activity especially compounds 3, 4, 8, 9, 15, and 17 which showed better activity than diclofenac as the reference drug. Compounds 3, 8, 9, 13, and 15–17 were less ulcerogenic than indomethacine as the reference drug. Most of the synthesized compounds interacted with Tyr 385 and Ser 530 in molecular docking study with additional hydrogen bond for compound 17 . Compound 17 showed good selectivity index value of 11.1 for COX‐1/COX‐2 inhibition in vitro.     

C‐phycocyanin protects against ethanol‐induced gastric ulcers in rats: Role of HMGB1/NLRP3/NF‐κB pathway

Gastric ulcer is a widespread inflammatory disease with high socio‐economic burden. C‐phycocyanin is one of the active constituents of Spirulina microalgae, and although it is well known for its antioxidant and anti‐inflammatory properties, its protective effects against gastric ulcer have not yet been identified. High‐mobility group box 1 (HMGB1) is a nuclear protein that, once secreted extracellularly, initiates several inflammatory reactions, and it is involved in the pathogenesis of gastric ulcer. The aim of the present study was to investigate the anti‐inflammatory and anti‐ulcerogenic effects of C‐phycocyanin against ethanol‐induced gastric ulcer targeting HMGB1/NLRP3/NF‐κB pathway. Ulcer induction showed increase in HMGB1 expression through activation of nucleotide‐binding domain and leucine‐rich repeat‐containing protein 3 (NLRP3) inflammasome and nuclear factor kappa p65 (NF‐κB p65). Moreover, oxidative stress and inflammatory markers were elevated in the ulcer‐treated group compared to the normal control group. However, pre‐treatment with C‐phycocyanin significantly reduced HMGB1 expression via suppression of NLRP3/NF‐κB, oxidative markers, IL‐1β, tumour necrosis factor‐α (TNF‐α) and ulcer index value. These results were consistent with histopathological and immunohistochemistry examination. Thus, C‐phycocyanin is a potential therapeutic strategy with anti‐inflammatory and anti‐ulcerogenic effects against ethanol‐induced gastric ulcer.     

Synthesis and pharmacological evaluation of 3‐(4‐chloro phenyl)‐2‐substituted‐3H‐quinazolin‐4‐ones as analgesic and anti‐inflammatory agents

A new series of 3‐(4‐chloro phenyl)‐2‐substituted‐3H‐quinazolin‐4‐ones were synthesized by reacting the amino group of 2‐hydrazino‐3‐(4‐chloro phenyl)‐3H‐quinazolin‐4‐one with different aldehydes and ketones. The compounds were investigated for their analgesic activity in albino mice, and for their anti‐inflammatory and ulcerogenic activities in Wistar rats. All test compounds exhibited analgesic and anti‐inflammatory activities. Compound VA2 (2‐(1‐ethylpropylidene‐hydrazino)‐3‐(4‐chloro phenyl)‐3H‐quinazolin‐4‐one) showed moderately more potent analgesic activity and compound VA3 (2‐(1‐methylbutylidene‐hydrazino)‐3‐(4‐chlorophenyl)‐3H‐quinazolin‐4‐one) showed moderately more potent anti‐inflammatory activity when compared with the reference standard, diclofenac sodium. The test compounds showed only mild ulcerogenic side effects when compared with aspirin. Drug Dev Res 69: 226–233, 2008 ©2008 Wiley‐Liss, Inc.     

Effect of non‐prohibited drugs on the phase II metabolic profile of morphine. An in vitro investigation for doping control purposes

The potential consequences of drug‐drug interaction on the strategies adopted by anti‐doping laboratories to report an adverse analytical finding for morphine were investigated. We evaluated in vitro the effects of 14 drugs on the principal metabolic pathways of morphine. The selected drugs are among those most commonly used by the athletes, none of them presently included in the World Anti‐Doping Agency (WADA) Prohibited List. The non‐prohibited drugs included 4 antifungals (fluconazole, itraconazole, ketoconazole, and miconazole), 6 benzodiazepines (alprazolam, bromazepam, clonazepam, lorazepam, lormetazepam, and triazolam), and 4 non‐steroidal anti‐inflammatory drugs (diclofenac, ibuprofen, ketoprofen, and nimesulide). The in vitro assays were based on the use of either human liver microsomes or uridine 5’‐diphospho‐glucuronosyl‐transferases. Morphine and its glucuronides were determined by developed liquid chromatography–mass spectrometry procedure after dilution with an aqueous solution containing their deuterated isotopologues as internal standards. Morphine is mainly excreted as phase II metabolites: about 70% of the parent compound is found to be biotransformed by UGT2B7 to morphine‐3‐glucuronide (6065%) and morphine‐6‐glucuronide (5‐10%). A reduction of the enzymatic activity of the UGT2B7 was recorded in the presence of 9 of the 14 drugs under investigation (ketoconazole, miconazole, itraconazole, diclofenac, ibuprofen, clonazepam, lorazepam, lormetazepam, and triazolam), with a consequent significant reduction of the levels of the glucuronide metabolites. This phenomenon in vivo may affect the rate of the urinary excretion of morphine with the risk of reporting “false negative” results, especially in case of results close to the decision limit value set by WADA.     

In silico approaches and chemical space of anti‐P‐type ATPase compounds for discovering new antituberculous drugs

Tuberculosis (TB) is one of the most important public health problems around the world. The emergence of multi‐drug‐resistant (MDR) and extensively drug‐resistant (XDR) Mycobacterium tuberculosis strains has driven the finding of alternative anti‐TB targets. In this context, P‐type ATPases are interesting therapeutic targets due to their key role in ion homeostasis across the plasma membrane and the mycobacterial survival inside macrophages. In this review, in silico and experimental strategies used for the rational design of new anti‐TB drugs are presented; in addition, the chemical space distribution based on the structure and molecular properties of compounds with anti‐TB and anti‐P‐type ATPase activity is discussed. The chemical space distribution compared to public compound libraries demonstrates that natural product libraries are a source of novel chemical scaffolds with potential anti‐P‐type ATPase activity. Furthermore, compounds that experimentally display anti‐P‐type ATPase activity belong to a chemical space of molecular properties comparable to that occupied by those approved for oral use, suggesting that these kinds of molecules have a good pharmacokinetic profile (drug‐like) for evaluation as potential anti‐TB drugs.     

Novel Conjugates of Aspirin with Phenolic Acid as Anti‐inflammatory Agents Having Significantly Reduced Gastrointestinal Toxicity

A series of novel conjugates of aspirin with natural phenolic acid antioxidants connected through a diol linker were designed and synthesized as potential bifunctional agents combining antioxidant and anti‐inflammatory activity for reducing gastrointestinal toxicity. In general, the conjugates were found to be efficient antioxidants and many of them demonstrated much more potent anti‐inflammatory activity than aspirin. Among them, 5a and 5b which bear the best anti‐inflammatory activity exhibited significantly reduced ulcerogenic potency and toxicity compared to aspirin. However, it is evident that the anti‐inflammatory activity of these dual‐acting molecules in vivo, was not simply consistent with their antioxidant ability in vitro.     

3‐(3‐Ethylphenyl)‐2‐substituted hydrazino‐3H‐quinazolin‐4‐one Derivatives: New Class of Analgesic and Anti‐Inflammatory Agents

A new series of 3‐(3‐ethylphenyl)‐2‐substituted hydrazino‐3H‐quinazolin‐4‐ones were synthesized by reacting the amino group of 2‐hydrazino‐3‐(3‐ethylphenyl)‐3H‐quinazolin‐4‐one with a variety of aldehydes and ketones. The title compounds were investigated for analgesic, anti‐inflammatory and ulcerogenic index behavior. The compound 2‐(N′‐3‐pentylidene‐hydrazino)‐3‐(3‐ethylphenyl)‐3H‐quinazolin‐4‐one ( AS2 ) emerged as the most active compound in exhibiting analgesic activity and the compound 2‐(N′‐2‐pentylidene‐hydrazino)‐3‐(3‐ethylphenyl)‐3H‐quinazolin‐4‐one ( AS3 ) emerged as the most active compound in exhibiting anti‐inflammatory activity; and these compounds are moderately potent when compared with the reference standard diclofenac sodium. Interestingly, the test compounds showed only mild ulcerogenic potential when compared with aspirin.     

Novel ketoprofen–antioxidants mutual codrugs as safer nonsteroidal anti‐inflammatory drugs: Synthesis,kinetic and pharmacological evaluation

Ketoprofen belongs to one of the most common nonsteroidal anti‐inflammatory drugs (NSAIDs) but its clinical usefulness has been restricted due to the high incidence of gastrointestinal complications. The release of reactive oxygen species (ROS) in NSAIDs therapy plays a major role in causing gastric complications. Antioxidants not only prevent gastric ulceration and lipid peroxidation but also preserve glutathione‐type peroxidase (GPO) activity. Therefore, the present study investigates the utility of combining anti‐inflammatory and antioxidant properties of two different compounds in a single molecule to form a series of 16 ketoprofen–antioxidant mutual codrugs. The free carboxylic group, which is believed to be one of the reasons for gastric toxicity of ketoprofen, was masked temporarily by simple and double esterification with alcoholic/phenolic–OH of natural antioxidants. In simple esterification, ketoprofen is directly linked to natural antioxidants ( IIa–h ) in the hope to obtain drugs free of gastric side effects. In an attempt to improve the in vivo lability, as well as gastric side effects, the double ester codrugs, that is, ketoprofen–antioxidant through the glycolic acid spacer (–CH₂COO; IIIa–h ), have also been designed and synthesized. The synthesized codrugs were characterized by IR, ¹H NMR, ¹³C NMR, mass spectroscopy and elemental analysis. The in vitro hydrolysis studies showed the lowest hydrolysis (highest stability) in acidic pH 1.2, whereas moderate hydrolysis was seen at pH 7.4 and significant hydrolysis in 80% human blood plasma, as indicated by their t_1/2. The pharmacological evaluation results indicate that these ketoprofen–antioxidant mutual codrugs showed the retention of anti‐inflammatory and analgesic activity with a significant reduction in the ulcer index.     

Preclinical pharmacokinetic and pharmacodynamic evaluation of thiazolidinone PG15: an anti‐inflammatory candidate

Objectives Novel 5‐benzilidene thiazolidinones have been synthesized and exhibited anti‐inflammatory activity. In this work one of the compounds of the thiazolidinone chemical series, (5Z,E)‐3‐[2‐(4‐chlorophenyl)‐2‐oxoethyl]‐5‐(1H‐indol‐3‐ ylmethylene)‐thiazolidine‐2,4‐dione (PG15) was investigated aiming to determine the drug's anti‐inflammatory potential in pre‐clinical studies. Methods Methods used included the in‐vitro inhibition of cyclooxygenase‐1 and ‐2, in‐vivo evaluation of anti‐inflammatory activity by air pouch and peritonitis models and the pharmacokinetic profile after intravenous (3 mg/kg) and oral (3 and 6 mg/kg) dosing to rats. Key findings A two‐compartment model with a fast distribution and an elimination half‐life of 5.9 ± 3.8 h described the PG15 plasma profile after intravenous dosing. PG15 showed an erratic and rapid absorption following oral administration with peak concentrations between 0.5 and 1 h. PG15 0.1 μM inhibited more than 30% and 13% of purified cyclooxygenase‐1 and ‐2 activity in vitro, respectively. A lack of dose dependency was observed for the anti‐inflammatory effect in the dose range investigated (0.8–50 mg/kg), with a maximum of 67.2 ± 4.6% inhibition of leucocyte migration in the carrageenan‐induced air pouch model obtained with the 3 mg/kg dose, similar to that observed for indometacin 10 mg/kg. Conclusions The erratic absorption of PG15 observed after oral dosing could explain the lack of anti‐inflammatory dose dependency.     

Synthesis,analgesic, anti‐inflammatory and ulcerogenic index activities of novel 2‐methylthio‐3‐substituted‐5,6‐dimethyl thieno [2,3‐d] pyrimidin‐4(3H)‐ones

A variety of novel 2‐methylthio‐3‐substituted amino‐5,6‐dimethyl thieno [2,3‐d] pyrimidin‐4(3H)‐ones were synthesized by reacting 3‐amino‐2‐methylthio‐5,6‐dimethyl thieno [2,3‐d] pyrimidin‐4(3H)‐one with different aldehydes and ketones. The starting material 3‐amino‐2‐methylthio‐5,6‐dimethyl thieno [2,3‐d] pyrimidin‐4(3H)‐one was synthesized from 2‐amino‐3‐carbethoxy‐4,5‐dimethyl thiophene. The compounds were investigated for their analgesic activity in albino mice, and for their anti‐inflammatory and ulcerogenic index activities in Wistar rats. The compound 2‐(1‐ethylpropylideneamino)‐2‐methylthio‐5,6‐dimethyl thieno [2,3‐d] pyrimidin‐4(3H)‐one (AS2) showed the most potent analgesic activity of the series. It also showed more potent anti‐inflammatory activity when compared to the reference standard, diclofenac sodium. The test compounds showed only mild ulcerogenic potential when compared to aspirin. Drug Dev Res 68:134–142, 2007. © 2007 Wiley‐Liss, Inc.     

Nefopam analgesia and its role in multimodal analgesia: A review of preclinical and clinical studies

Nefopam is a non‐opioid, non‐steroidal, centrally acting analgesic drug used to prevent postoperative pain, primarily in the context of multimodal analgesia. This paper reviews preclinical and clinical studies in which nefopam has been combined with opioids, non‐steroidal anti‐inflammatory compounds, and paracetamol. This report focuses on the literature during the last decade and discusses the translational efforts between animal and clinical studies in the context of multimodal or balanced analgesia. In preclinical rodent models of acute and inflammatory pain, nefopam combinations including opioids revealed a synergistic interaction or enhanced morphine analgesia in six out of seven studies. Nefopam combinations including non‐steroidal anti‐inflammatory drugs (NSAIDs) (aspirin, ketoprofen or nimesulide) or paracetamol likewise showed enhanced analgesic effects for the associated compound in all instances. Clinical studies have been performed in various types of surgeries involving different pain intensities. Nefopam combinations including opioids resulted in a reduction in morphine consumption in 8 out of 10 studies of severe or moderate pain. Nefopam combinations including NSAIDs (ketoprofen or tenoxicam) or paracetamol also demonstrated a synergic interaction or an enhancement of the analgesic effect of the associated compound. In conclusion, this review of nefopam combinations including various analgesic drugs (opioids, NSAIDs and paracetamol) reveals that enhanced analgesia was demonstrated in most preclinical and clinical studies, suggesting a role for nefopam in multimodal analgesia based on its distinct characteristics as an analgesic. Further clinical studies are needed to evaluate the analgesic effects of nefopam combinations including NSAIDs or paracetamol.     

Synthesis and pharmacological evaluation of novel derivatives of anti‐inflammatory drugs with increased antioxidant and anti‐inflammatory activities

The role of reactive oxygen species in inflammatory processes has been well documented, while several antioxidant compounds have been shown to exhibit anti‐inflammatory activity. We designed novel compounds as potential agents that combine enhanced antioxidant and anti‐inflammatory activities. Derivatives of indomethacin, diclofenac, tolfenamic acid, and ibuprofen, four widely used nonsteroidal anti‐inflammatory drugs, with cysteamine, a polar antioxidant molecule, were synthesized. The compounds were evaluated for their effect on free radical processes (protection against rat hepatic microsomal lipid‐peroxidation and interaction with the stable free radical 1,1‐diphenyl‐2‐picrylhydrazyl), as well as on carrageenan‐induced inflammation (mouse paw edema inhibition). Furthermore, ulcerogenicity tests in rats were performed in order to evaluate the gastrointestinal irritation of the novel indomentacin derivative. It was found that all compounds were very potent antioxidants in vitro; they could inhibit lipid peroxidation very significantly, having IC₅₀ values ranging from 55 to 510 μM, while they could also interact ∼90% with DPPH at equimolar concentrations. We attribute these activities to their sulfhydryl group, as well as to their increased lipophilicity compared to cysteamine. Furthermore, the derivatives demonstrated significant anti‐inflammatory activity, comparable to that of the parent molecules, while they showed significantly reduced ulcerogenic potency. Our results indicate that the combined pharmacological properties of these new derivatives may prove useful for the design and development of novel cytoprotective/anti‐inflammatory molecules with potentially important therapeutic applications. Drug Dev. Res. 47:9–16, 1999. © 1999 Wiley‐Liss, Inc.     

Phycocyanin liposomes for topical anti‐inflammatory activity: in‐vitro in‐vivo studies

Objectives The aim of this work was to investigate the anti‐inflammatory activity of C‐phycocyanin (C‐PC) on skin inflammation after topical administration and the influence of liposomal delivery on its pharmacokinetic properties. Methods Liposomes of different size and structure were prepared with different techniques using soy phosphatidylcholine and cholesterol. Vesicular dispersions were characterised by transmission electron microscopy, optical and fluorescence microscopy for vesicle formation and morphology, dynamic laser light scattering for size distribution, and Zetasizer for zeta‐potential. C‐PC skin penetration and permeation experiments were performed in vitro using vertical diffusion Franz cells and human skin treated with either free or liposomal drug dispersed in a Carbopol gel. Key findings The protein was mainly localised in the stratum corneum, while no permeation of C‐PC through the whole skin thickness was detected. Two percent C‐PC‐encapsulating liposomes showed the best drug accumulation in the stratum corneum and the whole skin, higher than that of the corresponding free 2% C‐PC gel. Moreover, skin deposition of liposomal C‐PC was dose dependent since skin accumulation values increased as the C‐PC concentration in liposomes increased. The topical anti‐inflammatory activity of samples was evaluated in vivo as inhibition of croton oil‐induced or arachidonic acid‐induced ear oedema in rats. Conclusions The results showed that C‐PC can be successfully used as an anti‐inflammatory drug and that liposomal encapsulation is effective in improving its anti‐inflammatory activity.     

1-ethyl and 1-propylazacycloalkan-2-one ester prodrugs of ketoprofen. Synthesis,chemical stability,enzymatic hydrolysis,anti-inflammatory activity,and gastrointestinal toxicity

Six ketoprofen (CAS 22071-15-4) alkylazacycloalkan-2-one ester derivatives (I-VI) were synthesized and evaluated for their anti-inflammatory, analgesic, and ulcerogenic activities after oral administration. Furthermore these derivatives were assayed to determine in vitro their stability in pH 7.4 phosphate buffer and in simulated gastric fluid (pH 2.0 buffer) and their susceptibility to enzymatic cleavage in rat plasma. All the prodrugs showed a good stability both in pH 7.4 phosphate buffer and in pH 2.0 buffer, and they were readily hydrolyzed by rat plasma. Esters I-VI showed an anti-inflammatory activity, determined as the percent of inhibition of carrageenan-induced edema, similar to that of ketoprofen, although at higher doses. They were significantly less irritating to the gastric mucosa than the parent drug. In the mouse acetic acid induced writhing assay, the prodrugs exhibited, following acute administration, a good analgesic activity.