Sulindac is a nonsteroidal anti-inflammatory agent (NSAIA) of the arylalkanoic acid class that is marketed in the U.S. by Merck as Clinoril. Like other NSAIAs, it may be used in the treatment of acute or chronic inflammatory conditions. Sulindac is a prodrug, derived from sulfinylindene, that is converted in vivo to an active sulfide compound by liver enzymes. The sulfide metabolite then undergoes enterohepatic circulation; it is excreted in the bile and then reabsorbed from the intestine. This is thought to help maintain constant blood levels with reduced gastrointestinal side effects. Some studies have shown sulindac to be relatively less irritating to the stomach than other NSAIA's except for drugs of the cyclooxygenase-2 (COX-2) inhibitor class. The exact mechanism of its NSAIA properties is unknown, but it is thought to act on enzymes COX-1 and COX-2, inhibiting prostaglandin synthesis.

Sorbinil (also known as CP-45,634), an aldose reductase inhibitor that has been in phase III clinical trials in preventing the development of diabetic retinopathy and neuropathy in persons with insulin-dependent diabetes. However, this research has been discontinued. It is also known, that sorbinil is oxidatively metabolized to a potentially toxic intermediate.

Ranirestat (AS-3201, SX-3030, SX-3202) is an oral aldose reductase inhibitor. (-)-enantiomer (AS-3201) is 10 times more potent in inhibition of the aldose reductase and 500 times more potent in the in vivo activity than the corresponding (+)-enantiomer (SX-3202). Ranirestat is being developed by Dainippon Sumitomo Pharma (formerly Dainippon Pharmaceutical) for the treatment of diabetic complications, primarily diabetic neuropathy. Ranirestat is a well-tolerated front-line inhibitor. It reproducibly exhibits some degree of measurable objective beneficial outcomes in diabetic neuropathy.

Ponalrestat is the inhibitor of aldehyde reductase 2 from a number of sources. Ponalrestat blunted Prostaglandin F2 alpha synthesis by preadipocytes in basal and stimulated conditions. Ponalrestat suppresses IL-1 production both in vitro and in vivo, and inhibits the cachectic symptoms induced by colon26 adenocarcinoma in mice, suggesting that ponalrestat has a therapeutic potential for the treatment of cancer cachexia. In a 4-week study of 29 neuropathic diabetics treated with ponalrestat peripheral neuropathy did not improve during treatment. In a 6-week study of 21 diabetics without neuropathy, although vagal function improved in patients with autonomic neuropathy.

Aldose reductase-IN-1 is an inhibitor of aldose reductase

Lidorestat is a highly potent and selective aldose reductase inhibitor with good oral bioavailability that is reported to improve nerve conduction and reduce cataract formation. Lidorestat reduced mortality rates in hAR transgenic mice. Mice receiving lidorestat had similar survival rates as nonhAR-expressing diabetic mice. Lidorestat treatment did not affect plasma lipids, glucose, or weights of diabetic mice. Drugs such as lidorestat will improve human health by reducing the production of toxic products of the polyol pathway. Lidorestat was developed for the treatment of diabetic complications, including neuropathy, retinopathy, cataracts, nephropathy.

Protocatechuic acid (3,4-dihydroxybenzoic acid, PCA) is a simple phenolic acid. It is found in a large variety of edible plants and possesses various pharmacological activities. This bioactive compound is famous for its biological properties and pharmacological activities such as: antioxidant, antibacterial, anticancer, antiulcer, antidiabetic, antiaging, antifibrotic, antiviral, anti-inflammatory, analgesic, antiatherosclerotic, cardiac, hepatoprotective, neurological and nephroprotective. The neuroprotective effects of PCA, extracted from Alpinia oxyphylla, on H2O2 resulted in apoptosis and oxidative stress in cultured PC12 cells. Apoptotic cell death by H2O2 was dose-dependent. Enhanced effect of PCA on protecting PC12 cells against apoptosis, augmented glutathione (GSH) level and an increase in catalytic activity was investigated by flow cytometric analysis. In cytotoxic assays, PCA causes cell death in HepG2 cancerous cell line of liver showing that PCA stimulates the c-Jun N-terminal kinase (JNK) and p38 subgroups of the mitogen-activated protein kinase (MAPK) family. Treatment with PCA decreased OVA-induced airway hyper-responsiveness to inhaled methacholine. Cell inflammation and mucus hypersecretion was also decreased by PCA. Thus, PCA can be useful for treating asthma. Experimental studies strongly support the role of protocatechuic acid in the prevention of neurodegenerative processes, including Alzheimer's and Parkinson's diseases, due to its favorable influence on processes underlying cognitive and behavioral impairment, namely accumulation of the β-amyloid plaques in brain tissues, hyperphosphorylation of tau protein in neurons, excessive formation of reactive oxygen species and neuroinflammation.

Isovitexin (apigenin-6-C-glucoside), an isomer of vitexin, is found in plants such as pigeon pea, Passiflora, bamboo, mimosa, wheat leaves, rice hull of Oryza sativa and others. Isovitexin is poorly absorbed in the gastrointestinal tract. The highest level of intravenously administrated isovitexin was examined in kidney, liver, lung, and lowest in the brain. Isovitexin helps to stimulate apoptotic cell death and autophagy of various cancer cells through the upstream regulation of Bax, PARP, p-JNK, and MAPK and the downstream regulation of the caspases Bcl-2 and ERK1/2. Isovitexin has been proved to have various activities, such as anti-oxidant, anti-inflammatory, anti-Alzheimer's disease and others.

Sylvatesmin is a furofuran lignin isolated from Forsythia suspense, Osmanthus fragrans and other plants. It protected LDL from lipid peroxidation and demonstrated free radical scavenging activity. Molecular modeling showed that sylvatesmin exhibited the highest inhibition of aldose reductase. In nutritive hyperlipidemia mice fed with high-cholesterol in vivo, the serum levels of blood TG and LDL-C were remarkably down-regulated by sylvatesmin. In vitro, sylvatesmin exhibited anti-inflammatory and anti-cancer activity.