Methylselenocysteine is a part of the mammalian physiology and is a well-tolerated, versatile and economical antiangiogenic agent. This compound participated in clinical trial to determine if vitamin supplementation with this compound could restore disruption of circadian rhythm in shift workers. The preclinical efficacy of methylselenocysteine has shown the combination of methylselenocysteine with androgen deprivation therapy can be useful for the treatment of advanced prostate cancer.

Sabeluzole (previously known as R 58 735) was developed for the treatment of Alzheimer's disease. It reached phase II clinical trials in Canada and Belgium before its development was discontinued. This drug possibly acts as N-methyl-D-aspartate (NMDA) receptor antagonist. In addition, the effect of sabeluzole on sleep, breathing and daytime symptoms was investigated in 13 patients with obstructive sleep apnea. Besides, no beneficial effect of sabeluzole was shown on peripheral nerve function in patients at an early stage of diabetic polyneuropathy.

Flindokalner (BMS 204352; MaxiPost™) is a neuroprotective agent with potential in the treatment of stroke developed by Bristol-Myers Squibb. Flindokalner is a potent and effective opener of two important subtypes of neuronal potassium channels, the calcium-activated, big-conductance potassium channels (K(Ca) channels) and voltage-dependent, non-inactivating potassium channels known as KCNQ channels. Flindokalner significantly reduced cortical infarct volume in a animal models of stroke. Flindokalner failed to show superior efficacy in acute stroke patients compared to placebo in a Phase III study.

Licostinel (ACEA 1021) is a potent competitive antagonist at the glycine site on the N-methyl-D-aspartate (NMDA) receptor. The robust efficacy of glycine/NMDA antagonists, such as ACEA 1021, in animal model of brain ischemia, together with good safety profile in animal models and in clinical trials, suggested that this class of NMDA antagonists should have good chance of success in the clinic as neuroprotectants. The clinical trial of ACEA 1021 for stroke was discontinued, mainly due to low solubility and lack of metabolism of the drug that led to the observation of crystals in the urine of some of the patients. In vivo ACEA 1021 reduced the rate of propagation of cortical spreading depression, an effect consistent with blockade of NMDA receptors. ACEA 1021 also decreased audiogenic myoclonus in resuscitated rats following cardiac arrest, and the minimum alveolar concentration for halothane, effects which suggest a reduction of excitatory amino acid neurotransmission. ACEA 1021 crosses the blood-brain barrier and blocks the pathophysiologic consequences of NMDA receptor overstimulation. It was neuroprotective with a favorable therapeutic window in models of transient and permanent cerebral ischemia, epilepsy and pain.

AstraZeneca developed disufenton (NXY-059), a free radical trapping agent, for the treatment of ischaemic stroke and other brain injuries. Nevertheless, large clinical trial (3306 versus 1722 patients) was neutral, providing no evidence for the efficacy of disufenton sodium in patients with stroke. One study using rat cortical brain slices concluded that NXY-059 improved neuronal survival. However, another study in mouse neuroblastoma cells reported no effect. Another study reported that NXY-059 restored endothelial blood-brain. Histological analyses revealed several therapeutic advantages associated with disufenton sodium treatment following acute acoustic trauma, including reductions in inner and outer hair cell loss; reductions in acute acoustic trauma-induced loss of calretinin-positive afferent nerve fibers in the spiral lamina; and reductions in fibrocyte loss within the spiral ligament. However, AstraZeneca terminated the development program.

Nicoxamat (nicotinohydroxamic acid) is a uricosuric drug that increased urinary excretion of urea and depressed urease activity in the stomach and the colon. Patients receiving nicoxamat showed significant improvement in blood ammonia levels as compared to patients receiving neomycin. In a double-blind clinical trial, 24 patients with the advanced chronic liver disease received 1.2 g of the drug daily. Nicoxamat induced some side effects, such as mild diarrhea, constipation, and anorexia.

Elsibucol (AGI-1096) is a phenolic intracellular antioxidant with anti-inflammatory and antiproliferative properties. In vitro, elsibucol inhibited the inducible expression of vascular cell adhesion molecule (VCAM)-1, E-selectin, and monocyte chemoattractant protein (MCP)-1 in endothelial cells and tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta secretion from lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells. It also inhibited serum-stimulated proliferation of aortic smooth-muscle cells. In vivo, elsibucol demonstrated anti-inflammatory properties in a murine delayed-type hypersensitivity model. In hypercholesterolemic animals, elsibucol inhibits atherosclerosis and preserves endothelial healing following arterial injury. Elsibucol development for the prevention of transplant rejection has been discontinued.

Sopromidine is a neuroprotective drug. Sopromidine is a potent and stereoselective isomer of the achiral H2-agonist impromidine. The chiral impromidine isomer sopromidine is of special interest as the (R)-configurated compound behaves as gpH2R agonist, whereas the (S)-configurated counterpart is devoid of agonist activity. Both Sopromidine and its S enantiomer acted as antagonists of histamine at H3-autoreceptors with similar potencies (Ki = 5.6 X 10(-8) M and 4.5 X 10(-8) M), whereas Sopromidine acted as an H2-receptor agonist and the S-enantiomer as an H2-receptor antagonist.

Tenilsetam (CAS 997: ( /-)-3-(2-thienyl)-2-piperazinone), a cognition-enhancing drug successfully used for the treatment of patients suffering from Alzheimer's disease. According to the mechanism proposed, it inhibits advanced glycation end-product (AGE) formation. The beneficial effect of tenilsetam in Alzheimer's disease could come from the interference with AGE-derived crosslinking of amyloid plaques and a decreased inflammatory response to diminished activation of phagocytosing microglia. In addition was shown, that the long-term treatment with tenilsetam inhibited the formation of acellular capillaries without correcting pericyte loss. Was suggested that tenilsetam could be useful for the treatment of early diabetic retinopathy, but then these studies were discontinued.

Argimesna (also known as arginine 2-mercaptoethanesulfonate) is a sulfhydryl group-containing molecule, which has no effect on glutathione status or on the total thiol pool, but is an uroprotective agent. Argimesna was investigated for the prevention of haemorrhagic cystitis from ifosfamide (IFO), but these studies were discontinued