Nicaraven is a hydroxyl radical scavenger with antivasospastic and neuroprotective effects. Chugai (the Japanese subsidiary of Roche) is developing nicaraven (Antevas), a water-soluble antioxidant, for the potential treatment of disorders caused by acute cerebrovascular diseases. A registration application was filed in April 1995, and in April 2002, nicaraven was still awaiting registration in Japan. By August 2002, Chugai had filed an NDA in Japan for the additional indication of subarachnoidal bleeding.

Telupidine (GR53992B), a dihydropyridine derivative is a calcium channel blocker. This is an antihypertensive and cardiovascular agent. Information about the current use of this compound is not available.

Semotiadil (also known as sesamodil or SD 3211) is a (+)-(R)-stereoisomer, the corresponding (−)-(S)-stereoisomer is called levosemotiadil. Semotiadil, a benzothiazine derivative was developed as a novel Ca2+ channel blocker with antiplatelet activity. Experiments on rodents have revealed that the drug had an advantage in the treatment of angina with regard to long-lasting action and selectivity for coronary artery and myocardium. In addition, semotiadil improved survival of rats with monocrotaline-induced pulmonary hypertension: comparison with diltiazem. Semotiadil was studied in phase II clinical trials for the treatment of angina pectoris and hypertension in Europe, and in Japan for the treatment of arrhythmias. However, the further development of semotiadil has now been discontinued.

Fostedil (KB-944) is a phosphonic acid derivative with potent vasodilator activity. KB-944 has been demonstrated to produce long lasting coronary vasodilator and hypotensive effects in conscious and anesthetized dogs; increase coronary blood flow in isolated, blood perfused heart preparations of dogs; and reduce systemic pressure in conscious normotensive and hypertensive rats. Slow channel calcium entry blockade is thought to contribute to the vasodilator activity of KB-944. Fostedil is longer acting in hypertensive animals than either nifedipine or diltiazem suggesting a potential clinical advantage for this compound. Unexpectedly, fostedil was shown to produce atrial fibrillation in 3 of 10 hypertensive patients in a placebo controlled study. Fostedil had been in phase II clinical trials for the treatment of angina pectoris. However, this research has been discontinued.

Dexverapamil (R-verapamil) is an enantiomer of verapamil. R-isomer behaved as an inhibitor of multidrug-resistant protein MRP1 (involved in the cancer cell multidrug resistance phenotype). It was developed by Knoll (BASF Pharma) as a chemosensitiser and/or modulator of multidrug resistance for use in combination with cancer chemotherapy. Dexverapamil was undergoing phase II clinical studies in France, Italy, Spain, United Kingdom and the US in patients with various cancers. It was also undergoing phase I clinical trials in Japan where it was licensed to Mitsui and Mitsui Toatsu Chemicals. However, development was discontinued. Dexverapamil (R-verapamil) has been developing by AGI therapeutics for the treatment of Irritable bowel syndrome however development was discontinued.

IPROTIAZEM is a vasodilator.

Levemopamil is a novel compound of the phenylalkylamine class of calcium channel blockers, possesses exceptionally high blood-brain barrier penetrability characteristics. It has a potent antagonistic action on serotonin 5-HT2-receptors. Activation of these receptors stimulates inositol phospholipid hydrolysis that can lead to the release of Ca2+ from intracellular stores as well as protein kinase C activation. Levemopamil thus has the potential for blocking deleterious increases of intracellular calcium arising from both intracellular stores and from the extracellular space. Levemopamil reduce both infarct size and extent of neuronal injury following permanent focal or transient global ischemia. The acute effect of bilateral clamping of carotid arteries on local cerebral blood flow was measured in the presence and absence of levemopamil in a separate group of rats. The data suggest that pretreatment with levemopamil reduces impairment in spatial behaviour and that this effect seems not related to the compound's cerebral vasodilatory action, but to direct neuronal mechanisms.

Fantofarone (SR 33557) is a non-dihydropyridine calcium antagonist with a novel site of action in the L-type Ca2+ channel. Fantofarone is capable of significantly modifying the cardiovascular function without increasing heart rate. Fantofarone was being developed for the treatment of angina pectoris, arrhythmias and hypertension.

Dexniguldipine (B8509-035, (-)-(R)-niguldipine) is a new dihydropyridine derivative, that exerts selective antiproliferative activity in a variety of tumor models and, in addition, has a high potency in overcoming multidrug resistance. Dexniguldipine is ( - )-(R)-enantiomer of niguldipine, of which the ( )-(S)-enantiomer shows pronounced cardiovascular hypotensive activity due to its high affinity for the voltage-dependent Ca2 channel. As compared with the (S)-enantiomer, the (R)-enantiomer has a 40-fold lower affinity for the Ca 2 channel and, accordingly, only minimal hypotensive activity in animal pharmacology models. Dexniguldipine have shown antiproliferative activity in several tumor cell lines, but the concentrations necessary to inhibit growth have varied by several orders of magnitude between cell lines. Initial results of preclinical investigations for the evaluation of the mechanism of its antiproliferative activity demonstrate that dexniguldipine interferes with intracellular signal transduction by affecting phosphoinositol pathways, protein kinase C expression, and intracellular Ca 2 metabolism. In a series of human tumor xenografts in vitro, dexniguldipine demonstrated selective antiproliferative activity against several tumor types, e.g., melanoma and renal-cell carcinoma. Striking results were obtained in a hamster model, in which neuroendocrine lung tumors could be completely eradicated by 20 weeks of oral treatment with 32.5mg/kg dexniguldipine, whereas Clara-cell-type lung tumors were not affected. In in vitro studies, dexniguldipine has been found to bind to P-glycoprotein (P-gp) and to enhance the cytotoxicity of chemotherapeutic agents such as doxorubicin and etoposide in several cell lines The synergistic effect may well be associated with the reversal of multidrug resistance (MDR) related to the activity of P-gp. In the clinical therapy of cancer, resistance to many cytostatic drugs is a major cause of treatment failure. However, the high potency of dexniguldipine (about 10-fold as compared with that of verapamil in vitro) and its low cardiovascular activity provide the opportunity to achieve blood or tumor concentrations that might be high enough to overcome Mdr 1 resistance in patients without producing dose-limiting cardiovascular effects.

Tiapamil (also known as Ro 11-1781) is a dithiane derivative patented by Hoffmann-La Roche, F., und Co., A.-G. as calcium-channel antagonist useful for myocardial infarction treatment. Tiapamil, like verapamil, inhibited in a concentration-dependent manner Ca2+-induced contractions in isolated, K+-depolarized preparations of rat renal artery, dog coronary artery and rabbit main pulmonary artery. The inhibitory effects of Tiapamil can be overcome by raising the Ca2+ concentration of the bath fluid. In the rabbit main pulmonary artery, Tiapamil reduces 45Ca influx into the K+-depolarized vascular smooth muscle cells. Tiapamil inhibits the slow potentials in partially depolarized guinea-pig papillary muscles. Tiapamil decreases contractile force in isolated guinea-pig atria and papillary muscles, as well as in isolated cat hearts. Tiapamil also reduces heart rate and increases coronary flow in these preparations. Tiapamil doubled coronary artery blood flow in the coronary sinus blood without producing major changes in blood pressure and heart rate in anesthetized dogs. Tiapamil did not affect contractions of isolated guinea-pig ileum, rat stomach strips or rat vas deferens in response to various stimulants. Tiapamil have no major effects on renal water and electrolyte excretion, on autonomic nerves and receptors, on pain perception and on the central nervous system. Acute, subacute, and chronic toxicity studies demonstrate low toxicity for Tiapamil with no tendency for accumulation. In clinical trials, Tiapamil effectively lowers systolic and diastolic blood pressure, but have no effects on heart rate