Isbufylline is a xanthine derivative. This compound exhibits remarkable antibronchospastic properties both in in vitro and in vivo (after oral or intravenous administration) experimental models. Isbufylline is significantly more effective than theophylline in antagonizing bronchospasms elicited by spasmogens (capsaicin, arachidonic acid, PAF and antigen) which mainly act by a local release of biologically active substances proposed to be involved in the pathogenesis of asthma. Isbufylline, unlike theophylline, possesses little or no CNS excitatory properties. Isbufylline exerts a greater inhibitory activity than theophylline on total phosphodiesterase activity in the rat lung.

Foretinib is an orally available multikinase inhibitor that targets c-MET and VEGFR2 with high affinity, which may result in the inhibition of tumor angiogenesis, tumor cell proliferation and metastasis. Foretinib is an experimental drug candidate for the treatment of cancer. It was in Phase II trials for the treatment breast cancer, non-small cell lung cancer, gastric cancer, head and neck cancer and papillary renal-cell carcinoma. The most frequent adverse events of any grade associated with foretinib were fatigue, hypertension, gastrointestinal toxicities, and nonfatal pulmonary emboli.

Befloxatone (MD-370,503) is a reversible inhibitor of monoamine oxidase A that was developed by Synthelabo for the treatment of depression, social phobias, and panic disorders. This drug participated in phase III clinical trials in France for depression. In addition participated in phase II for smoking cessation, anxiety disorders. Befloxatone has a good safety profile, lacking sedative, convulsant, anticholinergic and cardiovascular effects. However, all studies were discontinued.

Terbogrel, an agent having two pharmacodynamic actions, namely inhibition of thromboxane A2 synthase and antagonism of the thromboxane A2 receptor. The antithrombotic effect of terbogrel was dose-dependent and was associated with enhanced prostacyclin production. The drug was studied for the treatment of peripheral vascular disorders, pulmonary hypertension, and thrombosis. Terbogrel participated in phase II clinical trial to investigate its safety and efficacy in patients with primary pulmonary hypertension, however, this study was discontinued due to terbogrel’s induction of leg pain.

Caracemide is a nonspecific inhibitor of macromolecules affecting the synthesis of DNA, RNA, and proteins. Caracemide is an active inhibitor of ribonucleotide reductase as evidenced in the Novikoff tumor model. These inhibitory effects are concentration-dependent with 70 percent of DNA synthesis inhibited by a drug concentration of 1 mkM with a 4 h incubation. However, RNA and protein synthesis inhibition require a concentration of 50-100 mkM. DNA strand breaks were observed only at high in vivo concentrations of 100 mkM. The antineoplastic activity of caracemide was observed in the P388 murine model and in mammary (MX-I) and colon (CX-1) human tumor xenographs implanted in the subrenal capsules of athymic mice. In the MX-1 mammary tumor, a single daily injection provided greater activity than an intermittent schedule. Caracemide was inactive against murine L1210 leukemia, B16 melanoma, Lewis lung carcinoma, CD8FI mammary carcinoma and Colon 38. The toxicity on phase I studies was frequent but generally mild. Of note, significant central nervous system dysfunction manifested by lethargy, depression, and confusion occurred in some and was not predictable. In phase I studies Caracemide failed to demonstrate efficacy in patients with advanced renal cell cancer and advanced large bowel cancer.

Brequinar is a synthetic quinolinecarboxylic acid analogue with antineoplastic properties. Brequinar inhibits the enzyme dihydroorotate dehydrogenase, thereby blocking de novo pyrimidine biosynthesis. This agent may also enhance the in vivo antitumor effect of antineoplastic agents such as 5-FU. Brequinar had been in phase II clinical trials by Bristol-Myers Squibb for the treatment of cancer and transplant rejection. However, this research has been discontinued. Brequinar had been also in preclinical studys for the treatment of cytomegalovirus infections. However, this research has been discontinued.

Schering published xanthine PDE5 inhibitors with amino substituents in the imidazole 2-position, such as Dasantafil. Dasantafil, also known as SCH-446132, is a PDE5A inhibitor potentially for the treatment of erectile dysfunction. It had been in phase II clinical trials but there is no report for this compound recently.

Benafentrine (also known as AH 21-132), an inhibitor of the phosphodiesterase (PDE) III and IV isoenzymes, had an anti-allergic effect and was studied for the treatment of allergic bronchial asthma. However, the development of the drug was discontinued at phase I.

Atiratecan (previously known as CH4556300 or TP300), the prodrug of a topoisomerase 1 inhibitor, CH0793076. Atiratecan has been studied in phase II clinical trials to treat cancers (e.g., colorectal cancer; gastric cancer; esophageal cancer), but these studies were suspended.

Furegrelate (previously known as U-63557A), a selective orally active thromboxane synthase inhibitor, with potential for the treatment of various diseases including hypertension, thrombosis, and renal disorders, arrhythmias, but these studies were discontinued.