Nitraquazone (TVX 2706) is an phosphodiesterase inhibitor with antiinflammatory action. It strongly enhances the increase in intracellular levels of cyclic AMP caused by appropriate effectors in all systems tested so far. EC50 values are in the submicromolar range. The effect is apparently neither due to an increased responsiveness of the hybrid cells for an effector like prostaglandin E1 nor to an increased activity of adenylate cyclase, but to an inhibition of both low and high affinity cyclic AMP phosphodiesterases. Half-maximal inhibition of enzyme activity is obtained at 10 uM TVX 2706. TVX 2706 does not interfere with the calmodulin activation of phosphodiesterase. Nitraquazone affected cytokine production by PHA-stimulated human blood cells. Nitraquazone was active in reducing the production of IL-5 (IC50 = 0.8 uM), while its potency against IL-2, GM-CSF and IFN-gamma was 3-6 times lower.

TNP-470 (AGM-1470, (3R,4S,5S,6R)-5-methoxy-4- [(2R,3R)-2-methyl-3-(3-methyl-2-butenyl) -oxiranyl]-1-oxaspiro[2,5]oct-6-yl(chloroacetyl) carbamate) is an anti-angiogenic, semisynthetic analogue of fumagillin, a known antibiotic secreted by the fungus Aspergillus fumigatus fresenius, which is under clinical development for the treatment of cancer by Takeda Chemical Industries Ltd. in Japan and TAP Pharmaceuticals, Inc. in the United States. TNP-470 binds to and irreversibly inactivates methionine aminopeptidase-2 (MetAP2), resulting in endothelial cell cycle arrest late in the G1 phase and inhibition of tumor angiogenesis. This agent may also induce the p53 pathway, thereby stimulating the production of cyclin-dependent kinase inhibitor p21 and inhibiting angiogenesis. In early clinical reports, TNP-470 is tolerated up to 177 mg/m(2) with neurotoxic effects (fatigue, vertigo, ataxia, and loss of concentration) being the principal dose-limiting toxicity (DLT). TNP-470 is being evaluated in Phase I-II trials in the US in patients with Kaposi’s sarcoma, cervical cancer, breast cancer, brain cancer, prostate cancer and renal cell carcinoma.

Quilostigmine (also known as NXX-066) is an isoquinolinecarboxylate patented by Hoechst-Roussel Pharmaceuticals Inc as a memory enhancer. Quilostigmine acts as acetylcholinesterase inhibitor and studies as a potential drug for treating Alzheimer’s disease. Quilostigmine is well absorbed from the gastrointestinal tract, but the oral bioavailability poor to moderate in rats and dogs because of pre-systemic metabolism. In preclinical studies has demonstrated activity in animal models of memory function. In clinical trials, Quilostigmine was well tolerated in healthy subjects up to a single dose of 64 mg and multiple doses of 60 mg QD for seven days

Amiflamine is a selective and reversible inhibitor of monoamine oxidase (MAO) type A which exerts a preferential effect on serotonin (5-HT) catabolism. The (+)-enantiomer is the active stereoisomer. In a series of p-aminosubstituted phenethylamines, the ( + )-enantiomer of the compound amiflamine (4-dimethylamino-2-a-dimethylphenethylamine) was found to be a potent, selective, and reversible MAO type A inhibitor. Amiflamine (FLA 336(+] and its two metabolites, FLA 788(+) and FLA 668(+) were found to be competitive inhibitors of the activity of monoamine oxidase-A in homogenates of human hypothalamus and liver obtained at autopsy. Ki values, determined at pH 7.2, were 1.3, 0.3 and 22 uM (liver) and 0.8, 0.2 and 14 uM (hypothalamus) for amiflamine, FLA 788(+) and FLA 668(+), respectively. Monoamine oxidase-B activity was only weakly inhibited by the compounds. This initial phase I study in six normal subjects showed that the new MAO inhibitor amiflamine can be tolerated in single oral doses up to 80 mg without significant pharmacologic effects. Doses up to 60 mg were tolerated without any subjective or objective effects.

Anacetrapib is a CETP inhibitor being developed by Merck to treat hypercholesterolemia (elevated cholesterol levels) and prevent cardiovascular disease. Anacetrapib is a cholesterol ester transfer protein (CETP) inhibitor that blocks the transfer of cholesterol from highdensity lipoprotein to other lipoproteins. This results in an increase in high-density lipoprotein cholesterol (HDL-C) and a decrease in lowdensity lipoprotein cholesterol (LDL-C), which may reduce the development of atherosclerosis. Anacetrapib has not been approved for sale in Canada or the United States. Clinical evidence to support the use of anacetrapib for dyslipidemia has been reported in two clinical trials. REVEAL is an ongoing, large-scale phase 3 trial evaluating the effectiveness of anacetrapib with a statin for the secondary prevention of major coronary events in patients who have a history of cardiovascular disease. Results are anticipated in January 2017.

Enzastaurin is a serine/threonine kinase inhibitor that showed antiangiogenic, antiproliferative, and proapoptotic properties in vitro and antitumor activity in vivo in a xenograft Waldenström macroglobulinemia (WM) model. Enzastaurin (LY317615) is a potent PKCβ selective inhibitor. Enzastaurin suppresses angiogenesis and was advanced for clinical development based upon this antiangiogenic activity. Enzastaurin suppresses tumor growth through multiple mechanisms: direct suppression of tumor cell proliferation and the induction of tumor cell death coupled to the indirect effect of suppressing tumor-induced angiogenesis. Enzastaurin is an orally administered drug that was intended for the treatment of solid and haematological cancers. Enzastaurin had shown encouraging preclinical results for the prevention of angiogenesis, inhibition of proliferation and induction of apoptosis as well as showing limited cytotoxicity within phase I clinical trials. However, during its assessment in phase II and III clinical trials the efficacy of enzastaurin was poor both in combination with other drugs and as a single agent. Eli Lilly discontinued development of enzastaurin after top-line data from the double-blind, international Phase III PRELUDE trial in 758 DLBCL patients showed that enzastaurin missed the primary endpoint of improving DFS vs. placebo.

Diniprofylline is a vasodilator, broncholytic agent and respiratory stimulant used in severe respiratory insufficiencies.

An orally bioavailable inhibitor of cyclin-dependent kinases (CDKs) and thropomyosin receptor kinase A (TRKA), with potential antineoplastic activity. CDK2/TRKA inhibitor PHA-848125 AC potently inhibits cyclin-dependent kinase 2 (CDK2) and exhibits activity against other CDKs including CDK1 and CDK4, in addition to TRKA. Inhibition of these kinases may result in cell cycle arrest and apoptosis of tumor cells that express these kinases. Milciclib is currently in phase II clinical trials for thymic carcinoma, glioma and liver cancer. The most common adverse events are nausea and asthenia, vomiting, myasthenic syndrome, dehydration, hypophosphatemia, cytolytic hepatitis and plantar fasciitis.

Evandamine is an anti-inflammatory agent.

Proadifen is an inhibitor of drug metabolism and cytochrome P450 enzyme system activity. It stimulated the release of prostacyclin (PGI2) from the rabbit aorta, bovine aorta and human umbilical vein in vitro, but had no effect on cultured smooth muscle from the bovine aortic media. In human platelets, proadifen inhibited prostaglandin and thromboxane production induced by A23187, thrombin, and ADP. Proadifen might thus constitute the prototype of a new class of antiplatelet drugs.