AMG-837 is an orally bioavailable partial agonist of the GPR40 (EC50 value 13.5 nM for AMG 837 stimulated Ca2 flux in CHO cells expressing human GPR40) with a superior pharmacokinetic profile. AMG837 stimulated robust glucose-dependent insulin secretion (EC50 value 142±20 nM) in isolated rodent islets, and lowered post-prandial glucose in normal rats. Acute administration of AMG-837 lowered glucose excursions and increased glucose stimulated insulin secretion during glucose tolerance tests in both normal and Zucker fatty rats. The improvement in glucose excursions persisted following daily dosing of AMG 837 for 21-days in Zucker fatty rats. Preclinical studies demonstrated that AMG-837 was a potent GPR40 partial agonist which lowered post-prandial glucose levels. AMG-837 exhibits a potential utility for the treatment of type 2 diabetes. Amgen removed AMG-837 from Phase I clinical trials due to concerns over toxicity.

CL-316243 is a selective and highly specific β3-adrenoceptor agonist. CL 316243 possesses anti-obesity and anti-diabetic effects due to increasing brown adipose tissue thermogenesis and metabolic rate, and consequently may be useful for treating obesity as well as non-insulin-dependent diabetes mellitus in obese persons, without causing excessive side effects.

A-769662 stimulates partially purified rat liver AMPK with EC50 with 0.8 uM. A-769662 activates AMPK purified from multiple tissues and species in a dose-responsive manner with modest variations in observed EC50s. EC50s determined for A-769662 using partially purified AMPK extracts from rat heart, rat muscle, or human embryonic kidney cells (HEKs) are 2.2 uM, 1.9 uM, or 1.1 uM, respectively. A 4 hours treatment of primary rat hepatocytes with A-769662 dose-dependently increases ACC phosphorylation, which correlated inhibition of fatty acid synthesis with IC50 of 3.2 uM. A-769662 also inhibits fatty acid sythesis in mouse hepatocytes with IC50 with 3.6 uM. A-769662 activates AMPK both allosterically and by inhibiting dephosphorylation of AMPK on Thr-172, similar to the effects of AMP. A-769662 inhibits proteasomal function by an AMPK-independent mechanism. A-769662 affects the in vitro activity of purified 26S proteasomes but not the in vitro activity of purified 20S proteasomes. A-769662 has toxic effects on MEF cells. A recent research shows A-769662 inhibited cell proliferation and DNA synthesis.

CP 316819 is the selective glycogen phosphorylase inhibitor. CP 316819 has been extensively evaluated as antihyperglycemic agents for type 2 diabetes because of its potential to limit hepatic production of glucose from glycogen without inducing hypoglycemia. Under low glucose conditions, CP 316819 facilitates glycogen utilization in the brain, prevents neuronal cell death and maintains brain electrical currents.

Picein is a phenolic compound from mycorrhizal roots of Norway spruces (Picea abies). Picein moderately promoted adipogenesis of 3T3-L1 cells. Picein has being shown to be active against the rat small intestinal α-glucosidase.

AC-261066 is an agonist of retinoic acid receptor subtype β isoform 2 (RARβ2). Administration of AC-261066 to either wt mice in a model of HFD-induced T2D or to ob/ob and db/db mice reduces hyperglycaemia, peripheral insulin resistance and body weight. Furthermore, AC-261066 dramatically reduces steatosis, lipid peroxidation and oxidative stress in the liver, pancreas and kidneys of obese, diabetic mice. AC-261066 also lowers levels of mRNAs involved in lipogenesis, such as sterol regulatory element-binding transcription factor 1 (SREBP1) and fatty acid synthase, and increases mRNAs that mediate mitochondrial fatty acid β-oxidation, such as CPT1α, in these organs. AC-261066 lowers triglyceride levels in these organs, and in muscle. AC-261066 should be useful drug for T2D therapy and for treatment of hepatic steatosis.

Isoorientin is a common C-glycosyl flavone in the human diet. It has been isolated from several plant species, including Phyllostachys pubescens, Crataegus monogyna and Crataegus pentagyna, Patrinia villosa Juss, Drosophyllum lusitanicum, buckwheat, Arum palaestinum, and Rumex and Swertia. Isoorientin possesses significant anti-nociceptive and anti-inflammatory activities. Significantly protected PC12 nerve cells from 6-OHDA-induced apoptotic neurotoxicity and reduced the proliferation of HepG2 cells. Isoorientin showed anti-RSV (respiratory syncytial virus) activity.

Eleutheroside E is one of the active constituents of the Eleutherococcus senticosus (Rupr. & Maxim.) is also called Harms (ES), Acanthopanax senticosus, Siberian ginseng, or Gasiogapi in Korea. It is a diastereoisomer of Eleutheroside D. Eleutheroside E (EE) significantly decreased the inflammatory cell infiltration, pannus formation, cartilage damage, and bone erosion of collagen-induced arthritis mice, highlighting Eleutheroside E as a potential therapeutic agent for rheumatoid arthritis. Treatment of rat mesangial cells with Eleutheroside E markedly attenuated high glucose induced cells proliferation and in a dose-dependent manner. Intervention with EE also significantly blocked high glucose induced intracellular ROS production by decreasing NADPH oxidase activity. Intervention with EE also significantly blocked high glucose induced intracellular ROS production by decreasing NADPH oxidase activity. EE mediates the hyperglycemic effects of Eleutherococcus senticosus by regulating insulin signaling and glucose utilization. The beneficial effects of EE may provide an effective and powerful strategy to alleviate diabetes. Eleutheroside E exhibited weak inhibition against CYP2C9, CYP2E1 activity, and no effect on CYP2D6 and CYP3A4. The inhibition can result in the increase of the plasma concentration and toxicity of concomitant drugs, especially for those with narrow therapeutic windows such as warfarin, phenobarbital and phenytoin.

Balaglitazone, also known as DRF-2593; NNC-61-0645; NNC-61-2344; NN-2344; NNC-610645; NNC-612344, is an agonist of peroxisome proliferator-activated receptor (PPAR)γ. Balaglitazone plays an important role in the regulation of insulin, triglycerides and lipid metabolism. It is an attractive target for the therapy of Type II Diabetes. Balaglitazone is a partial agonist of PPARγ. It has showed potent effects on lowering blood glucose in various animal models. Balaglitazone 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. Balaglitazone exists as two enantiomers: BALAGLITAZONE, (S)- and BALAGLITAZONE, (R)-. A capillary electrophoresis method for separation of a racemic mixture of glitazone compounds has being used. The method separated the R and S enantiomers of balaglitazone, and showed that the samples contained an equal (50:50) quantity of the enantiomers as a mixture. The Rs for the separations were 3.5 for balaglitazone enantiomers.

Quebrachitol (QCT), a bioactive plant constituent, is a naturally occurring optically active cyclitols. QCT could serve as the starting material of inositol or its derivatives to participate in several important pathways and may act as a potential anticancer or antidiabetic drug lead to arrest or reverse these diseases. According to the literature reported before, QCT exerted its biological functions, by involving IP3 receptor, b-glucosidase, PAFR, COX2, nitric oxide synthase, and K(+)ATP channels. Quebrachitol reduces the gastric damage induced by ethanol and indomethacin. The potential of quebrachitol as a sugar substitute for diabetics has been investigated. Even though the early study reported that this methylcyclitol seems neither to prevent hypoglycemia nor to raise blood sugar content, another work showed that quebrachitol has hypoglycemic effects in hyperglycemic rats. Unfortunately, all three persons who took quebrachitol by mouth had fairly severe diarrhea.