PH-797804 is a diarylpyridinone inhibitor of p38alpha mitogen-activated protein. The drug was developed by Pfizer for the treatment of inflammatory diseases. PH-797804 is being tested in phase II of clinical trials in patients with COPD, osteoarthritis, rheumatoid arthritis and post-herpetic neuralgia.

ATB-346, being developed by Antibe Therapeutics, a Toronto-based pharmaceutical company, is a hydrogen sulfide-releasing non-steroidal anti-inflammatory drug (NSAID) that inhibits COX and suppresses prostaglandin production. ATB-346 exhibits anti-inflammatory, analgesic, antinociceptive, immunomodulatory, and neuroprotective activities. In vivo, this compound attenuates zymosan-induced inflammation, nociception, and immune signaling. ATB-346 also prevents ligature-induced periodontal bone loss and pathologies, potentially by suppressing increases in pro-inflammatory cytokine levels. Additionally, ATB-346 decreases edema and improves neurological function in animal models of traumatic brain injury (TBI). ATB-346 completed Phase 1 clinical studies in Q1 2015. To better understand the metabolism of ATB-346, Antibe conducted a radiolabeled study in rats at Covance Laboratories that was completed in Q4 2015. Antibe received approval from Health Canada in March 2016 to conduct a Phase 2 trial of ATB-346 in patients with osteoarthritis of the knee. Preclinical studies of ATB-346 for the treatment intestinal cancer; malignant melanoma; periodontal disorders are in progress.

ADL5859 (or ADL-5859) is Adolor Corporation developed a novel, oral compound that targets the delta opioid receptor. Delta receptor agonists are thought to offer benefits over other approaches to the management of pain. ADL-5859 was in the phase II of clinical trial for the treatment of neuropathic pain, acute pain, and pain due to osteoarthritis of the knee and for patients with osteoarthritis. Further development of this drug as potential pain treatments was discontinued.

PF-04457845 is a fatty acid amide hydrolase 1 inhibitor developed by Pfizer for the treatment of inflammatory and noninflammatory pain disorders. The drug was tested in phase II in patients with osteoarthritis of the knee, but found to have the same effect as placebo. It was also assessed in phase II clinical trial for its effect on marijuana withdrawal and Tourette syndrome.

Balicatib is a potent cathepsine K inhibitor that was developed for the treatment of knee osteoarthritis. The development of Balicatib was terminated in phase II due to the occurrence of skin rashes and rarer incidences of morphea-like skin changes.

GW406381 is an investigational, highly selective cyclooxygenase-2 (COX-2) inhibitor for inflammatory pain treatment. It showed effectiveness in animal models of central sensitization such as chronic constriction injury and capsaicin-induced hyperalgesia. It's effect was also evaluated in several clinical trials in patients with peripheral nerve injury (Phase I ), rheumatoid arthritis (Phase III), the signs and symptoms of osteoarthritis of the knee to control of pain and improvement in function (Phase III), and in treating the signs and symptoms of dental pain following third molar tooth extraction (Phase III). Possessing favourable pharmacokinetic profiles and analgesic activity in vivo, GW406381 have also demonstrated relatively high brain penetration in the rat compared with the clinically available compounds, which may ultimately prove beneficial in the treatment of pain.

Ligustrazine (tetramethylpyrazine) is a bioactive ingredient extracted from the widely-used Chinese herb, Chuanxiong. It inhibits of platelet aggregation, enhances of vessel dilation, increases cerebral blood flow and possesses neuroprotective properties. The injection solution of ligustrazine has been used especially in China to treat ischemic stroke, coronary heart disease, diabetic nephropathy, and knee osteoarthritis. Ligustrazine was also evaluated in clinical as a remedy for pressure sores, as a salvage agent for patients with non-Hodgkin's lymphoma, as a treatment for bronchial asthma and vertebrobasilar insufficiency.

Rosmarinic acid (α-o-caffeoyl-3,4-dihydroxyphenyllactic acid; RA) is a naturally occurring hydroxylated compound commonly found in species of the subfamily Nepetoideae of the Lamiaceae and Boraginaceae, such as Rosmarinus officinalis, Salvia officinalis, and Perilla frutescens. RA is biosynthesized from the amino acids L-phenylalanine and L-tyrosine by eight enzymes that include phenylalanine ammonia lyase and cinnamic acid 4-hydroxylase. Recently, RA and its derivatives have attracted interest for their biological activities, which include anti-inflammatory, anti-oxidant, anti-angiogenic, anti-tumor, and anti-microbial functions. Clinically, RA attenuates T cell receptor-mediated signaling, attenuates allergic diseases like allergic rhinitis and asthma, and 2,4-dinitrofluorobenzene-induced atopic dermatitis-like symptoms, protects from neurotoxicity, and slows the development of Alzheimer's disease. Rosmarinic Acid seems to be able to suppress 5-lipoxygenase and 5-HETE synthesis (a pro-inflammatory compound in the omega-6 metabolic chain). Rosmarinic acid appeared to be effective in suppressing allergies in a dose-dependent manner, with 30% of the placebo group reporting symptom relief compared to 55.6% of the 50mg group and 70% of the 200mg group.

Resveratrol, a natural non-flavonoid polyphenol, exhibits a wide range of beneficial properties as an anticancer agent, a platelet anti-aggregation agent, and an antioxidant, as well as its anti-aging, anti-inflammatory, antiallergenic. This compound is in phase III clinical trials in combination with carboxymethyl-β-glucan for improving nasal symptoms in children with pollen-induced allergic rhinitis. Also in phase III clinical trial in the treatment of painful knee osteoarthritis and in type 2 diabetic patients. It has been demonstrated that resveratrol may prevent type 2 diabetic by targeting Sirtuin type 1 (SIRT1), indicating that SIRT1 may be a novel therapeutic target for diabetes prevention.

Glucosamine is an amino sugar and a prominent precursor in the biochemical synthesis of glycosylated proteins and lipids. Glucosamine is part of the structure of the polysaccharides chitosan and chitin, which compose the exoskeletons of crustaceans and other arthropods, as well as the cell walls of fungi and many higher organisms. Glucosamine is one of the most abundant monosaccharides. It is produced commercially by the hydrolysis of crustacean exoskeletons or, less commonly, by fermentation of a grain such as corn or wheat. Oral glucosamine is a dietary supplement and is not a pharmaceutical drug. It is illegal in the US to market any dietary supplement as a treatment for any disease or condition. Glucosamine is marketed to support the structure and function of joints, and the marketing is targeted to people suffering from osteoarthritis. Commonly sold forms of glucosamine are glucosamine sulfate, glucosamine hydrochloride, and N-acetylglucosamine. Of the three commonly available forms of glucosamine, only glucosamine sulfate is given a "likely effective" rating for treating osteoarthritis. Glucosamine is often sold in combination with other supplements such as chondroitin sulfate and methylsulfonylmethane. Glucosamine, along with commonly used chondroitin, is not routinely prescribed to treat people who have symptomatic osteoarthritis of the knee, as there is insufficient evidence that this treatment is helpful. One clinical study over three years showed that glucosamine in doses of 1500 mg per day is safe to use. Glucosamine with or without chondroitin elevates the international normalized ratio (INR) in individuals who are taking the blood thinner, warfarin. It may also interfere with the efficacy of chemotherapy for treating cancer symptoms. Adverse effects may include stomach upset, constipation, diarrhea, headache, and rash. There are case reports of people who have chronic liver disease and a worsening of their condition with glucosamine supplementation. Glucosamine is naturally present in the shells of shellfish, animal bones, bone marrow, and fungi. D-Glucosamine is made naturally in the form of glucosamine-6-phosphate, and is the biochemical precursor of all nitrogen-containing sugars. Specifically in humans, glucosamine-6-phosphate is synthesized from fructose 6-phosphate and glutamine by glutamine—fructose-6-phosphate transaminase as the first step of the hexosamine biosynthesis pathway. The end-product of this pathway is uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), which is then used for making glycosaminoglycans, proteoglycans, and glycolipids. As the formation of glucosamine-6-phosphate is the first step for the synthesis of these products, glucosamine may be important in regulating their production; however, the way that the hexosamine biosynthesis pathway is actually regulated, and whether this could be involved in contributing to human disease remains unclear.