Etomoxir is an irreversible inhibitor of carnitine O-palmitoyltransferase (CPT) I. It inhibits fatty acid oxidation and fatty acid and cholesterol synthesis in an enantiomer-selective manner: only the R-enantiomer of etomoxir inhibits fatty acid oxidation, S-enantiomer inhibits fatty acid and cholesterol synthesis but not fatty acid oxidation. Etomoxir was studied for the treatment of congestive heart failure and type II diabetes, however, its development was discontinued.

Netoglitazone (also called MCC-555) is a hypoglycemic agent belonging to the thiazolidinedione group that exerts both peroxisome proliferator-activated receptor (PPAR) alpha and gamma agonist activity. It was developed by Mitsubishi-Tokyo (formerly Mitsubishi Chemical) as a potential treatment for type 2 diabetes due to the enhancement of insulin sensitivity. This drug was in clinical trial phase II but then was discontinued. In addition, was also investigated the behaviour of MCC-555 on colorectal cancer (CRC) cells and was revealed, that the drug had an effect on the early events of colon carcinogenesis and could be a potential preventive compound for CRC.

Balaglitazone is a second generation peroxisome proliferator-activated receptor (PPAR) gamma agonist with only partial agonistic properties. It passed phase III clinical trial for the treatment of type 2 diabetes. However, Dr. Reddy's Laboratories decided to terminate further clinical development of balaglitazone.

Oxfenicine is a CPT-1b-specific inhibitor. It must be transaminated to its active form, 4-hydroxyphenyl-glyoxylate, which is competitive with carnitine, preventing the formation of acylcarnitine. Because CPT-1b shows the highest sensitivity to 4-hydroxyphenyl-glyoxylate, inhibition of fatty acid oxidation by oxfenicine takes place selectively in those tissues that express this CPT isoform. It may be effective for treating noninsulin-dependent diabetes mellitus which is characterized by elevated fatty acid levels and obesity. In 1980 it was also tested in preclinical models of angina pectoris and ischemia.

SR 202 is an antagonist of peroxisome proliferator-activated receptor γ (PPARγ) transcriptional activity induced by troglitazone but not of basal PPARγ activity. It is selective for PPARγ, not affecting basal or agonist-induced transcriptional activity of PPARα, PPARβ, or the farnesoid X receptor (FXR). It inhibits PPARγ-dependent differentiation of preadipocyte 3T3-L1 cells in a dose-dependent manner. SR 202 (400 mg/kg) decreases the amount of weight gained and white adipose tissue mass accumulated by mice fed a standard or high-fat diet for ten weeks and is associated with lower PPARγ mRNA levels. It protects against high-fat diet-induced insulin resistance in wild-type mice and improves insulin sensitivity in ob/ob mice.

Tolimidone, Lyn protein-tyrosine kinase stimulant, is in phase II clinical by Melior Discovery and Bukwang for the treatment of type 2 diabetes. It is also in phase II clinical by Pfizer for the treatment of ulcer. However, this research has been discontinued.

Tagatose is a functional sweetener. It is naturally occurring and often found in dairy products. Tagatose is similar in texture and sweetness to sucrose (table sugar) but with only 38% of the calories. It is approved for use as a food additive as a low-calorie sweetener. Only 15 - 20 % of Tagatose is absorbed in the small intestines and metabolized similarly to sucrose; the bulk of ingested tagatose is fermented in the colon by bacteria producing short chain fatty acids which are subsequently absorbed and metabolized by the body without affecting insulin levels. Tagatose is being investigated by Spherix for the treatment of obesity and type II diabetes. Tagatose consumed orally significantly blunts the rise in plasma glucose seen after oral glucose in patients with diabetes mellitus in a dose-dependent manner without significantly affecting insulin levels. It has been suggested that Tagatose may act by attenuating the absorption of glucose in the intestines.

ZLN005 was developed as a novel small molecule, led to changes in peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) mRNA levels, glucose uptake, and fatty acid oxidation in L6 myotubes. ZLN005 exerted promising therapeutic effects for treating type 2 diabetes. ZLN005 increases fat oxidation and improves the glucose tolerance, pyruvate tolerance, and insulin sensitivity of diabetic db/db mice. In addition, was confirmed potential of PGC-1α as a drug target for the treatment of type 2 diabetes mellitus (T2DM) and metabolic syndromes.

Japanese scientists discovered AdipoRon during screening of a compound library. This drug is a selective agonist of adiponectin receptors 1 and 2, which activates 5′-adenosine monophosphate–activated protein kinase (AMPK) in cultured mammalian cells, an enzyme that is involved in many metabolic processes including the release of insulin, inhibition of lipid synthesis, and stimulation of glucose uptake. It was found, that after oral administration in mice AdipoRon effectively attenuated post-ischemic cardiac injury, thus could be a promising novel therapeutic approach treating cardiovascular complications caused by obesity-related disorders such as type 2 diabetes. In addition, recently investigation showed that AdipoRon has antiproliferative effects of adiponectin and may suppress the colorectal cancer cell growth.

APD668 is a novel, highly potent and orally active glucose-dependent insulinotropic receptor (GDIR) agonist intended to more efficiently stimulate insulin release by beta cells in response to elevated blood glucose levels, and to avoid hypoglycemia. Ortho-McNeil's initial clinical studies evaluated healthy volunteers and patients with type 2 diabetes in randomized, double-blind, placebo-controlled trials evaluating the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple (14 day) escalating doses of APD668. Based on the data from those studies, Ortho-McNeil has decided to put APD668 on hold and has advanced a potentially more potent Arena discovered GDIR agonist into preclinical development.