Apricoxib, (CS-706, 1) 2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole, a small-molecule, orally active, selective COX-2 inhibitor was discovered by investigators at Daiichi Sankyo in 1996. Apricoxib binds to and inhibits the enzyme cyclooxygenase-2 (COX-2), thereby inhibiting the conversion of arachidonic acid into prostaglandins. Apricoxib-mediated inhibition of COX-2 may induce tumor cell apoptosis and inhibit tumor cell proliferation and tumor angiogenesis. COX-related metabolic pathways may represent crucial regulators of cellular proliferation and angiogenesis. Clinical studies demonstrated potent analgesic activity and preclinical studies demonstrated good pharmacokinetics, pharmacodynamics and gastrointestinal tolerability. As an anticancer agent, preclinical studies demonstrated efficacy in biliary tract cancer models and colorectal carcinoma. Phase IIa trial data indicated that apricoxib was a potent analgesic in the treatment of pain in postoperative dental surgery. Apricoxib, a novel once-daily selective cyclooxygenase-2 inhibitor, was investigated in combination with erlotinib for recurrent stage IIIB/IV nonsmall cell lung cancer. Apricoxib plus erlotinib was well tolerated and yielded a 60% disease control rate. A phase II trial was investigating 400 mg/day apricoxib plus 150 mg/day erlotinib in patients selected based on change in urinary PGE-M. However, in 2015 development was abandoned due to poor clinical trial results.

Murabutide is a safe synthetic immunomodulator derived from muramyl dipeptide, the smallest bioactive unit of bacterial peptidoglycan. In contrast to muramyl dipeptide, Murabutide is devoid of pyrogenic activity and lacks somnogenic activity. Murabutide acts as a ligand for the intracellular receptor NOD2 and has the capacity to synergize with selected therapeutic cytokines to drive the release of Th1 cytokines. Murabutide has been found to suppress human immunodeficiency virus type-1 (HIV-1) replication, in macrophages, through regulated expression of cellular factors needed at different steps in the virus replication cycle.

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.

BN-2629 (also known as SJG-136 and SG2000), a dimeric pyrrolobenzodiazepine that binds in the minor groove of DNA and produces G-G interstrand cross-links via reactive N(10)-C(11)/N(10')-C(ll') imine/carbinolamine moieties. This drug was investigated in phase II clinical trials in patients with epithelial ovarian, primary peritoneal, or fallopian tube cancer, however, these studied were terminated because of the slow accrual. In addition, BN-2629 participated in phase I/II trial in participants with advanced chronic lymphocytic leukemia and acute myeloid leukemia, but Spirogen also terminated these studies.

Fallypride F-18 is a radiolabeled form of dual dopamine D2/D3 receptor antagonist. It is used as a PET tracer to characterize the distribution and binding potential of striatal and extrastriatal dopamine D2/D3 receptors in animals as well as in normal and diseased human brain.

Oxapropanium was studied as a cholinergic agent. Information about the current use of this compound is not available.

Licofelone (ML 3000) is a pyrrolizine derivative originally discovered by Merckle GmbH and developed by EuroAllaince with a unique pharmacological profile, which comprises optimal gastrointestinal tolerability and high analgesic and anti-inflammatory activity. These effects are due to balanced and selective inhibition of both cyclo-oxygenase and 5-lipoxygenase. Inhibition of 5-lipoxygenase may reduce the gastrointestinal toxicity associated with other non steroidal anti-inflammatory drugs, which only inhibit cyclooxygenase. Licofelone also has antipyretic and antiaggregatory properties. Clinical and preclinical trials were also undertaken for osteoarthritis, rheumatoid arthritis, asthma, pain and inflammation. However, development for these indications appear to have been discontinued.

Ocinaplon is anxiolytic in rodents and primates, including humans, with a magnitude of effect comparable to benzodiazepines. It was evaluated to treat Generalised anxiety disorder. The mechanism of action by which ocinaplon produces its anxiolytic effects is by allosteric modulating of GABA-A receptors. The serious adverse event detected in the ocinaplon group was icterus following transaminase elevations. Due to liver complications that occurred in Phase III, development of ocinaplon is discontinued.

Chlorsulfaquinoxaline is a halogenated derivative of sulfaquixonaline, an immunosuppressive and antifungal agent used in the control of coccidiosis in poultry, rabbit, sheep, and cattle. In vitro, Chlorsulfaquinoxaline acts as a topoisomerases IIα and IIβ poison, thus inhibiting DNA replication. Chlorsulfaquinoxaline shows good activity against human tumor cells in the human tumor colony-forming assay and subsequently has shown activity against murine and human solid tumors. No major objective antitumor responses was observed during Chlorsulfaquinoxaline Phase II clinical evaluation in non-small-cell lung cancer and metastatic colorectal cancer. Chlorsulfaquinoxaline was well tolerated with hypoglycemia being the most clinically significant toxicity.