Tenidap ([Z]-5-chloro-2,3-dihydro-3-[hydroxy-2-thienylmethylene]-2-oxo-1H-indole-1-carboxamide) is an oxindole derivative, a COX/5-LOX inhibitor and cytokine-modulating anti-inflammatory drug candidate that was under development by Pfizer as a promising potential treatment for rheumatoid arthritis. Tenidap shows potent inhibition of cyclooxygenase in vitro, that is of several magnitudes greater than 5-lipoxygenase inhibition. Lipoxygenase inhibition, however, has been difficult to document in vivo because Tenidap is highly protein bound and free drug concentrations are below those necessary for 5-lipoxygenase inhibition. However, several in-vitro activities distinguish Tenidap from conventional cyclooxygenase inhibitors. As shown with stimulated human neutrophils, tenidap inhibits activation of collagenase, lysosomal enzyme secretion, and superoxide generation, as well as aggregation and adhesion to endothelium. Furthermore, unlike Non-steroidal anti-inflammatory drugs (NSAIDs), it lowers circulating C-reactive protein (CRP) concentrations by a magnitude equivalent to hydroxychloroquine and auranofin. This result suggests an effect on the synthesis and/or release of the cytokines known to induce the acute-phase protein response-namely, IL-1, IL-6, and TNF-alpha. Tenidap, like existing second-line drugs, lowers serum IL-6 concentrations, a property not shared by NSAIDs The cytokine inhibitory effect also includes reduced in-vitro concentrations of TNF-alpha and IL-1 from both RA synovium and peripheral blood mononuclear cells. There is no immunosuppressive effect of Tenidap in either animal or clinical studies. In clinical studies. The comparisons between tenidap and other second-line agents show that Tenidap produced a faster reduction in CRP than Auranofin. The rate of withdrawal because of inefficacy was similar (18-20%) in Auranofin and Tenidap groups. The quality of life using the arthritis impact measurement scales has also been assessed Scores were better with tenidap than with NSAID monotherapy, but equivalent to the second line plus NSAID combinations. Tenidap is registered in the United States, Netherlands, and Italy but is not marketed because marketing approval was rejected by the FDA in 1996 due to liver and kidney toxicity, which was attributed to metabolites of the drug with a thiophene moiety that caused oxidative damage.

Droxicam is a nonsteroidal anti-inflammatory drug that is a pro-drug of piroxicam. The mechanism of action of droxicam, as well as that of piroxicam, is that of inhibition of prostaglandin biosynthesis. Droxicam acts by inhibition of PGE2. Although it belongs to the oxicam family, it is characterised by being a pro-drug of piroxicam, the molecule undergoing conversion by hydrolysis once dissolved in the digestive tract. Droxicam was used for the relief of pain and inflammation in musculoskeletal disorders such as rheumatoid arthritis and osteoarthritis. Droxicam possesses considerable analgesic activity, of equal magnitude to that of piroxicam and notably greater than that of acetylsalicylic acid, dipyrone, phenylbutazone and isoxicam. The antipyretic activity of droxicam, studied by means of different tests, has shown itself to be clearly superior to that of acetylsalicylic acid, dipyrone and 4-aminoantipyrine. Droxicam acts as an inhibitor of ex vivo platelet aggregation in the dog. However, owing to hepatotoxicity, droxicam was withdrawn in many countries.

3-hydroxy-2-phenylcinchoninic acid (also known as oxycinchophen or earlier as HPC) was known as antidiuretic and has been specially found useful in cases of diabetes insipidus. Clinical studies of HPC revealed that this compound reduces water output in cases of diabetes insipidus, and this was reached not by direct action on the water reabsorbing element in the tubules of the kidney, but rather by the mediation of HPC on the pituitary system in the production of the antidiuretic hormone therein. The effect of HPC upon fever and arthritis on patients with rheumatic fever was dramatic. In addition, HPC cannot be considered as an antipyretic, but rather HPC should be considered as enhancing ins some way the output or activity of adrenal cortical hormones. HPC was shown rather toxic (toxic reaction were presented in 20 % of tested patients). That is why the development of this drug was stopped and is become study its derivatives.

Azapropazone is a non-steroidal anti-inflammatory drug. It is indicated for use in the treatment of rheumatoid arthritis, osteo-arthritis and gout. Gastro-intestinal disturbances, allergic skin rashes and photosensitivity, headache, vertigo, oedema and kidney impairment may occur. Gastro-intestinal bleeding and angioedema have been reported. Pre-treatment with this drug failed to modify plasma concentrations of phenobarbitone. Brain levels of imipramine or desmethyl imipramine were unaffected 60 minutes after oral administration of imipramine.

Lumiracoxib is a COX-2 selective inhibitor non-steroidal anti-inflammatory drug. On August 11, 2007, Australia's Therapeutic Goods Administration (TGA, the Australian equivalent of the FDA) cancelled the registration of lumiracoxib in Australia due to concerns that it may cause liver failure. New Zealand and Canada have also followed suit in recalling the drug. It has never been approved for use in the United States. Lumiracoxib has a different structure from the standard COX-2 inhibitors (e.g. celecoxib). It more closely resembles the structure of diclofenac (one chlorine substituted by fluorine, the phenylacetic acid has another methyl group in meta position), making it a member of the arylalkanoic acid family of NSAIDs. It binds to a different site on the COX-2 receptor than the standard COX-2 inhibitors. It displays extremely high COX-2 selectivity. The mechanism of action of lumiracoxib is due to inhibition of prostaglandin synthesis via inhibition of cyclooygenase-2 (COX-2). Lumiracoxib does not inhibit COX-1 at therapeutic concentrations. Lumiracoxib is used for the acute and chronic treatment of the signs and symptoms of osteoarthritis of the knee in adults.

Bufexamac is a nonsteroidal antiinflammatory drug (NSAID) used in topical formulations to treat dermatological diseases (eczema and dermatitis) and proctological conditions (haemorrhoids and anal fissure). Bufexamac-containing medicines have been available in EU Member States since the 1970s. In 2010 European Medicines Agency recommends revocation of marketing authorisations for bufexamac due to high risk of contact allergies. The phenolic bufexamac decomposition products could be the reason for its eczema-provoking properties frequently described in the literature. Bufexamac is a class IIb histone deacetylase (HDAC6, HDAC10) inhibitor. Bufexamac also triggered an HDAC6-independent, hypoxia-like response by stabilizing Hypoxia-inducible factor 1-alpha, providing a possible mechanistic explanation of its adverse, pro-inflammatory effects. Bufexamac was capable of specifically inhibiting leukotriene A4 hydrolase and attenuating lung inflammation in acute lung injury mouse model.

Tolfenamic acid is a selective COX-2 inhibitor, which was marketed in Europe for the treatment of acute migraine disorders. Tolfenamic acid is currently unavailable for human use, however, it may be prescribed for veterinary purposes.

Polmacoxib (trade name Acelex) is a nonsteroidal anti-inflammatory drug (NSAID) used to treat osteoarthritis. Polmacoxib is a novel NSAID that, due to its postulated dual inhibition of cyclooxygenase enzymes and Carbonic anhydrase -I/II, might limit the propensity for NSAID-induced hypertension and thereby attenuate associated cardiovascular risks. Polmacoxib did not elevate blood pressure in healthy volunteers or OA subjects in any of the previous clinical studies, including 4 Phase I and 1 Phase II trials. In Phase III clinical trials Polmacoxib was relatively well tolerated and demonstrated efficacy superior to placebo and noninferior to celecoxib after 6 weeks of treatment in patients with osteoarthritis. The results obtained during the 18-week trial extension with Polmacoxib were consistent with those observed during the 6-week treatment period, indicating that Polmacoxib can be considered safe for long-term use based on this relatively small scale of study in a Korean population. Polmacoxib approved for use in South Korea in February 2015.

Clofezone (Perclusone), an analgesic and anti-inflammatory agent, is a drug that was used to treat joint and muscular pain, mostly in rheumatic diseases. Clofezone is a compound preparation of phenylbutazone and clofexamide. Tolerance of Perclusone was very good, no side-effects were observed.

Diphenpyramide is a non-steroidal anti-inflammatory compound, that has been studied in degenerative and inflammatory arthropathies treatment. In animal tests, Diphenpyramide showed anti-inflammatory action as powerful as that of indomethacin or phenylbutazone, with major peripheral analgesic, antipyretic and uricosuric properties. The therapeutic index was more favorable than that of the reference compounds. Diphenpyramide inhibits the synthesis of inflammatory prostaglandins and antagonizes the mediators of inflammation, but does not affect platelet aggregation or blood clotting. The anti-inflammatory action of diphenpyramide has been extensively proven in clinical trials in which patients with various inflammatory conditions, mainly of a musculoskeletal nature, were treated. The overall therapeutic efficacy was over 80% with a high proportion of osteoarthritis. In double-blind studies, the efficacy of Diphenpyramide was significantly better than that of acetylsalicylic acid or indomethacin in osteoarthritis and comparable with that of naproxen. Side-effects were seldom reported, were mild and transient and mainly of a gastrointestinal nature.