Oleandrin is a toxic cardiac glycoside found in oleander (Nerium oleander L.). Along with neandrin it is primarily responsible for the toxicity of the sap of oleander. Oleandrin has been used for many years in China and Russia for its properties as a cardiac glycoside, for both suicidal and therapeutic purposes as in treatment of cardiac insufficiency. Because of its properties as a cardiac glycoside, oleandrin interferes in some essential processes within the cell, the most important of these being the inhibition of the Na-K ATPase. This protein enables the cell to exchange the cations Na+ and K+ between the intercellular and extracellular spaces by which, for instance, electronic signaling is made possible in nerve cells. Oleandrin binds to specific amino acids in the protein, causing it to lose its function. After depolarization of the cell in which Na+ flows into the cell, the Na+ cannot be transported back into the extracellular membrane, causing the sodium gradient to disappear. This gradient is the driving force for other transport proteins, such as the sodium-calcium exchanger, which plays an important role in cardiomyocytes. To make muscle contraction possible, a calcium influx from the extracellular fluid into the cell is crucial. After the muscle contraction, the calcium is normally pumped out of the cell and exchanged for sodium. When the sodium gradient is depleted, calcium cannot be pumped back and, as a consequence, accumulates in the cardiomyocyte. As a result of the high calcium concentration, actin and myosin filaments will bind stronger, unable to relax properly to make a new contraction possible. This may result in cardiac arrhythmias, in the worst case decreasing cardiac output and causing a shortage in oxygen supply in vital tissues. Apart from being a potent toxic compound, it may also be used in therapeutic ways. Both oleandrin and oleandrigenin, as well as their relatives, may be able to inhibit proliferation of tumor cells and stimulate their apoptosis as a result of the high concentration of intracellular calcium. In addition, it inhibits excretion of fibroblast growth factor 2 through membrane interaction and through inhibition of the Na,K-ATPase pump. However, there are no results from clinical testing on humans that support any use as a cancer treatment. Oleandrin has been reported to be lethal, but exact dosages are not fully documented. The fatal blood concentration of oleandrin has been estimated for humans to be approximately 20 ng/ml in decreased blood by extrapolation of intoxication symptoms. Symptoms present in poisoned animals include bloody diarrhea and colic, the latter especially in horses. Because the leaf itself is quite bitter, only starving animals will be likely to eat the plant. The lethal dosage for animals is estimated to be about 0.5 mg/kg.

JTK-853, a piperazine derivative, is a non-nucleoside inhibitor of the hepatitis C virus (HCV) RNA-dependent RNA polymerase. It is under development for the treatment of hepatitis C virus infection.

Vatiquinone is the international non-proprietary name for Edison Pharmaceuticals’ EPI-743, an orally bioavailable small molecule being developed by the company for inherited mitochondrial diseases. EPI-743 is a member of the para-benzoquinone class of drugs. The mechanism of action of EPI-743 involves augmenting the synthesis of glutathione, optimizing metabolic control, enhancing the expression of genetic elements critical for cellular management of oxidative stress, and acting at the mitochondria to regulate electron transport. EPI-743 is a compound being developed by BioElectron (previously known as Edison Pharmaceuticals) to treat Friedreich’s ataxia (FA), a rare, autosomal recessive genetic disorder. The regulation of oxidative stress is disturbed in people with FA. EPI-743 targets NADPH quinone oxidoreductase 1 (NQO1), helping to increase the biosynthesis of glutathione, a compound essential for the control of oxidative stress. The drug does not target any FA-specific biochemical pathways directly, but helps to improve the regulation of cellular energy metabolism in general. Vatiquinone has been investigated for the treatment and prevention of retinopathy, rett syndrome, parkinson's disease, noise-induced hearing loss, and methylmalonic aciduria and homocystinuria, Cblc type. The FDA previously granted orphan drug designation for Edison’s EPI-743 to treat inherited respiratory chain diseases of the mitochondria and Friedreich’s ataxia. The company received orphan drug designation for EPI-743 from the Japanese Ministry of Health, Labour and Welfare and European Medicines Agency Committee on Orphan Products for the treatment of Leigh syndrome.

SCH 900271 was studied as a potent nicotinic acid receptor agonist for the Treatment of Dyslipidemia. This compound participated in a phase II clinical trial to evaluate its efficacy and safety in participants with primary hypercholesterolemia or mixed hyperlipidemia. However, apparently, the further development of SCH 900271 had been discontinued.

PSI-697 is a quinoline derivative patented by Wyeth, John, and Brother Ltd. as a selectin inhibitor useful for the treatment of acute coronary syndromes. Surface expression of P-selectin on activated platelets induces the formation of platelet-monocyte aggregates and promotes vascular inflammation and thrombosis. In cell-based assays, PSI-697 dose-dependently inhibits the binding of human P-selectin to human P-selectin glycoprotein ligand-1. In preclinical trials, PSI-697, promotes thrombus resolution and decreases inflammation in a baboon model of venous thrombosis. Animals receiving PSI-697 demonstrated significantly increased plasma D-dimer levels versus low-molecular-weight-heparin and control animals six hours post thrombus induction. Unfortunately, in clinical trials, PSI-697 did not inhibit basal or stimulated platelet-monocyte aggregate formation in humans

S 3304 is a potent, orally active, noncytotoxic inhibitor of matrix metalloproteinases, primarily MMP-2 and MMP-9 that was developed by Shionogi as an anticancer agent. This drug has prolongs survival in mice xenografts and was well tolerated in healthy volunteers. S 3304 had completed phase I clinical trials for patients with locally advanced non-small cell lung cancer and with advanced solid tumors, however, the company had discontinued the further development of S 3304.

Sepranolone (UC1010) is a GABA-A modulating steroid antagonist (GAMSA) and does not antagonize the effect of GABA itself or other GABAA agonists like benzodiazepines and barbiturates. The interaction of neuroactive steroids (i.e., allopregnanolone and Sepranolone) with GABA-A receptor is particularly important in mood disorders. For example, allopregnanolone administration decreased saccadic eye velocity in healthy female volunteers and induced sedation and these effects were diminished by simultaneous sepranolone administration. Thus, allopregnanolone effects are antagonized by its isomer sepranolone. UC1010 reduces symptom severity and impairment significantly more efficiently than placebo in women with a well-defined, pure premenstrual dysphoric disorder. No severe adverse events were reported during the UC1010 treatment and safety parameters (vital signs and blood chemistry) remained normal during the study. It was revealed also that increases in ring A-reduced progesterone metabolites, particularly Sepranolone, are associated with chronic fatigue syndrome.

Dexmecamylamine (TC-5214, also known, as S isomer of mecamylamine) is a positive allosteric modulator of α4β2 neuronal nicotinic receptors, rather than an open-channel blocker. It was evaluated as a potential adjunct treatment for patients with major depressive disorder (MDD). TC-5214 was generally well tolerated, however, the studies were not supportive of an antidepressant effect for TC-5214 in patients with MDD and inadequate response to prior antidepressant therapy. The Phase 2b clinical trial of TC-5214 for the treatment for overactive bladder (OAB) revealed the high dose of TC-5214 demonstrated mixed results on the co-primary endpoints by providing a statistically significant reduction in micturition frequency and an improvement that did not reach statistical significance on episodes of urinary incontinence. As a consequence of these results, this drug was discontinuing further development of TC-5214 in OAB. The study for using TC-5214 in patients with refractory hypertension was also terminated.