Marizomib is a natural beta-lactone produced by the marine bacterium Salinispora tropica. Marizomib has a broad inhibition profile for the 20S proteasome and has been shown to inhibit the CT-L (beta5) CT-T-laspase-like (C-L, beta1) and trypsin-like (T-L, beta2) activities of the 20S proteasome. The drug is being tested in phase II clinical trials for the treatment of Multiple Myeloma and Malignant Glioma and in phase I in patients with Non-small Cell Lung Cancer, Pancreatic Cancer, Melanoma or Lymphoma

The monoterpene perillyl alcohol (POH) is a naturally occurring compound derived from citrus fruits, mint, and herbs. It exhibited chemotherapeutic potential against various malignant tumors in preclinical models and was being tested in clinical trials in patients with refractory advanced cancers. POH was formulated in soft gelatine capsules and orally administered to cancer patients several times a day on a continuous basis. However, such clinical trials in humans yielded disappointing results, also because of the large number of capsules that had to be swallowed caused hard-to-tolerate intestinal side effects, causing many patients to withdraw from treatment due to unrelenting nausea, fatigue, and vomiting. The clinical trials in Brazil have explored intranasal POH delivery as an alternative to circumvent the toxic limitations of oral administration. In these trials, patients with recurrent malignant gliomas were given comparatively small doses of POH via simple inhalation through the nose. Results from these studies showed, that this type of long-term, daily chemotherapy was well tolerated and effective. The precise mechanism of action is still undetermined, but it is known, that perillyl alcohol plays an important role in the process of hepatoma cell invasion and migration via decreasing the activity of Notch signaling pathway and increasing E-cadherin expression regulated by Snail. Another possible mechanism is included inhibition of Na/K-ATPase (NKA). The NKA α1 subunit is known to be superexpresses in glioblastoma cells (GBM) and POH acts in signaling cascades associated with NKA can control cell proliferation and/or cellular death.

Rabusertib is a Chk1 kinase inhibitor which was developed by ICOS for the treatment of cancer. The drug was tested in phase II of clinical trials for pancreatic cancer and non small cell lung carcinoma, but its development was discontinued. Now the drug is undergoing phase I trial in Japanese patients with solid tumors.

Nanterinone [UK 61260], a phosphodiesterase III inhibitor, was undergoing II evaluation with Pfizer in the US for the treatment of heart failure. Nanterinone is a positive inotropic and balanced-type vasodilating drug, only partially based on phosphodiesterase III inhibition. Preliminary data from controlled studies suggest satisfactory long-term efficacy and safety.

Patamostat (E-3123) is a protease inhibitor in vivo and in vitro. Inhibitory activity was shown toward trypsin, thrombin, plasmin, cathepsin-B and kallikrein. Patamostat is effective toward experimental pancreatitis and disseminated intravascular coagulation (animal models).

Ridogrel is a dual action drug used for the prevention of systemic thrombo-embolism and as an adjunctive agent to thrombolytic therapy in acute myocardial infarction. Ridogrel, a combined thromboxane synthase inhibitor, and receptor antagonist is used with streptokinase as an adjunctive therapy to reduce the formation and size of blood clots. Blood clots can cause ischemic cardiac events (heart attacks). Ridogrel has the dual property of inhibiting the synthesis of thromboxane and blocking the receptors of thromboxane/prostaglandin/endoperoxides. It has been shown to accelerate the speed of recanalization and to delay or prevent reocclusion during systemic thrombolysis with tissue plasminogen activator (streptokinase). Ridogrel is a more potent antiplatelet agent than aspirin and might offer an advantage over aspirin as an adjunct to thrombolysis in patients suffering from acute myocardial infarction. While aspirin inhibits cyclooxygenase, the enzyme responsible for producing thromboxane, ridogrel inhibits thromboxane synthesis directly. Ridogrel has been studied primarily as an adjunctive agent to thrombolytic therapy in acute MI (AMI). Despite positive results from initial pilot studies, the largest clinical study, the Ridogrel versus Aspirin Patency Trial (RAPT) failed to demonstrate any advantage with this agent over aspirin. In the study of 907 patients with AMI, there was no difference in the primary endpoint of infarct vessel patency rate between those randomized to ridogrel (72.2%) or aspirin (75.5%). Various mechanisms are likely responsible for the results seen with ridogrel in clinical trials, including potentially ineffective thromboxane receptor inhibition with the concentrations of ridogrel used in human studies. As such, there currently are no clinical indications for preferential use of ridogrel over aspirin.

Edelfosine is a synthetic alkyl-lysophospholipid, a potent immunomodulator and an effective inhibitor of tumor cell proliferation. The cytotoxic effect of edelfosine has been evaluated in a large variety of both tumor (leukemic and solid) and normal cell types, showing a high degree of selectivity towards tumor cells. Like all alkyl-lysophospholipids, Edelfosine incorporates into the cell membrane and does not target the DNA. In many tumor cells, Edelfosine causes selective apoptosis, sparing healthy cells. Edelfosine can activate the Fas/CD95cell death receptor, can inhibit the MAPK/ERK mitogenic pathway and the Akt/protein kinase B (PKB) survival pathway. Edelfosine apoptosis-inducing abilities were studied with several types of cancer, among them multiple myeloma and non-small and small cell lung carcinoma cell lines. In vivo activity against human solid tumors in mice was shown against malignant gynecological tumor cells, like ovarian cancer, and against breast cancer. In vivo biodistribution studies demonstrated a “considerably higher” accumulation of Edelfosine in tumor cells than in other analyzed organs. Several clinical trials were conducted. Among them, a phase I trials with solid tumors or leukemias and phase II with non-small-cell lung carcinomas (NSCLC). In Phase II clinical trial for use of Edelfosine in treating leukemia with bone marrow transplants, it was found to be safe and 'possibly effective'. A phase II trial for the treatment of brain cancers was also reported. It showed encouraging results in stopping the growth of the tumor and a considerable improvement in the “quality of life” of the patients. A phase II trial on the effect of Edelfosine on advanced non-small-cell bronchogenic carcinoma had a “remarkable” “high proportion of patients with stationary tumor status” as result, stable disease after initial progression in 50% of the patients.

Etomoxir is an irreversible inhibitor of carnitine O-palmitoyltransferase (CPT) I. It inhibits fatty acid oxidation and fatty acid and cholesterol synthesis in an enantiomer-selective manner: only the R-enantiomer of etomoxir inhibits fatty acid oxidation, S-enantiomer inhibits fatty acid and cholesterol synthesis but not fatty acid oxidation. Etomoxir was studied for the treatment of congestive heart failure and type II diabetes, however, its development was discontinued.

Dimabefylline an antiasthmatic, bronchospasmolytic drug. Also, it might be used as coronary dilator, cardiac stimulant.

Eptastigmine or heptylphysostigmine is a competitive inhibitor of acetylcholinesterase. Eptastigmine leads to an improvement in the cerebral blood flow in the ischemic brain, excitatory and inhibitory effects on the gastrointestinal tract and to a protection from acute soman and diisopropylfluorophosphate intoxication. Eptastigmine, by either acute or chronic administration, has been found to have memory enhancing effects in different species of normal, aged and lesioned animals. It also restored to normal the age-related increase of EEG power without affecting spontaneous motor activity. Eptastigmine produces significant cognitive, clinical, and functional benefits in patients with probable Alzheimer's Disease. Although the cholinergic tolerability of eptastigmine was found to be favorable, its potential adverse hematologic effects limit its clinical utility.