Amitivir [LY217896], an amino thiadiazole derivative, is an inhibitor of the enzyme inosine monophosphate dehydrogenase. Amitivir has activity against several influenza A and B viruses. Amitivir possesses broad antiviral activity in vitro and in animal models against or thomyxo-and paramyxoviruses. In phase I studies with healthy volunteers, single doses of up to 500 mg were well tolerated and had predictable pharmacokinetics. Oral LY217896 was in trial for prevention of experimental influenza A virus infection and illness in humans. LY217896 was associated with asymptomatic rises in serum uric acid levels and was ineffective in modifying the virologic or clinical course of experimental influenza A (H1N1) virus infection. Amitivir development was discontinued.

Motapizone is a pyridazinone derivative patented by pharmaceutical company Nattermann, A., und Cie. G.m.b.H. as an antithrombotic and hypotensive agent. Motapizone ats as a potent inhibitor of the isoenzyme phophodiesterase type III. In preclinical studies potent antithrombotic and hypotensive properties of motapizone has been shown in rats, cats, and dogs. In normal human volunteers, single oral doses of motapizone up to 10 mg produced significant inhibition of platelet aggregation measured by the ex vivo method. These effects were dependent upon the dose of motapizone and associated with an increase in heart rate and a reduction in diastolic blood pressure.

Cilostamide (also known as OPC 3689) is a selective inhibitor of type III phosphodiesterases: PDE3A and PDE3B, which inhibits thrombin-induced platelet aggregation. Elevating intracellular cAMP has been shown to inhibit platelet function. cAMP interferes with platelet-activating signals, which leads to aggregation inhibition, but the precise mechanism is unclear. It is known, that inhibition of Akt phosphorylation leads to inhibition of phosphorylation of glycogen synthase kinase 3-beta (GSK-3beta), which is an effector of Akt. However, cAMP-elevating agents’ stimulated GSK-3beta phosphorylation at Ser9. The cAMP-elevating agent cilostamide did not directly affect the enzyme activity of PI3-kinase, and thus it has two effects on PI3K signaling: inhibition of Akt phosphorylation independent of PKA. And stimulation of GSK-3beta phosphorylation dependent on PKA.

Nafagrel [DP 1904, SR 96325] is a thromboxane A2 synthetase inhibitor that was undergoing clinical trials with Daiichi Seiyaku, now Daiichi Pharmaceutical, for the diabetic angiopathies, lupus nephritis and Raynaud's disease in Japan. However the development of Nafagrel has been discontinued.

Glenvastatin (HR780) is a synthetic HMG-CoA reductase (HMGCR) inhibitor. Like other statins, glenvastatin shows very low systemic bioavailability due to an extensive first pass effect at the intestinal and/or hepatic level. This is a positive trait, since the liver is the target organ for statins. Evidence has been found that glenvastatin protects the vascular endothelium from oxidant stress and inhibits the migration and proliferation of smooth muscle cells. In rabbits, long-term treatment with glenvastatin reduces the plasma cholesterol level, and decreases the liver cholesterol contents. There are no results of clinical trials for glenvastatin.

Lexacalcitol (KH1060) is over 100 times more active than 1alpha,25-dihydroxyvitamin D3 and is of potential interest in the treatment of psoriasis and other diseases characterized by accelerated cell growth and T lymphocyte activation, which was studied in the clinical trial. KH1060 also prevents type I diabetes in the preclinical investigation without significant effects on calcium or bone metabolism. In addition also was shown that neuroblastoma (NB) cell lines were more susceptible to growth inhibition by KH1060, suggesting its possible use in NB to potentiate the action of retinoids, which are in clinical use for this disease. The underlying biochemical reasons for the increased biological activity of KH1060 are unknown, but it can include 1) metabolic considerations in addition to explanations based upon 2) enhanced stability of KH1060-liganded transcriptional complexes.

Eprodisate (1,3-propanedisulfonate) is a negatively charged, sulfonated molecule of low molecular weight that has structural similarities to heparin sulfate; it is a glycosaminoglycan mimetic that binds to the glycosaminoglycan (GAG) binding site on serum A amyloid (AA) to prevent its interaction with glycosaminoglycan and arrest amyloidosis, or inhibit amyloid deposition. In nonclinical toxicity studies in two animal species (i.e., rat and dog), eprodisate was administered orally at doses of up to 2000 mg/kg/day for 39 weeks: eprodisate showed low toxicity potential at doses several fold higher than the anticipated clinical dose, was well tolerated upon chronic exposure and was found to be nonmutagenic and nonclastogenic. Furthermore, a series of safety pharmacology studies showed that eprodisate does not have any clinically significant effect on major organ function.

Bervastatin (also known as LS 2904), a synthetic HMG-CoA reductase inhibitor that was developed for the treatment of hyperlipidemia. However, information about further development is not available.

Amiglumide [CR 1795] is an amino acid derivative with cholecystokinin A antagonist activity. It has potential use for treating gastrointestinal disorders, pancreatitis and biliary dyskinesia. Amiglumide was developed in preclinical trials with Rottapharm in Italy.

Quazinone (also known as Ro 13-6438 ) is a cardiotonic and vasodilator drug which was developed and marketed in the 1980s for the treatment of heart disease. The positive inotropic response to Quazinone of the isolated guinea pig papillary muscle was accompanied by inhibition of myocardial phosphodiesterase (PDE) activity and elevation of intracellular cyclic AMP (cAMP) levels Quazinone had no effect on Na+, K+-stimulated or Ca2+-stimulated ATPase activity and did not influence the rate of calcium uptake in cardiac membrane vesicles. Quazinone caused a concentration-dependent increase in the upstroke velocity, overshoot, and duration of slow action potentials evoked in partially depolarized papillary muscles. Pretreatment of guinea pigs with reserpine did not prevent the effects of Quazinone on slow action potentials but slightly decreased its positive inotropic activity. In clinical trials, Quazinone induces dose-dependent hemodynamic changes, an increase in cardiac index combined with decreases in pulmonary capillary wedge pressure and systemic and pulmonary arterial pressures.