Tasidotin (also known as ILX-651), an orally active synthetic microtubule-targeted derivative of the marine depsipeptide dolastatin-15. It was suggested, that tasidotin has a unique mechanism of action. The drug inhibits cell proliferation by suppressing spindle microtubule dynamics through a reduction of the shortening rate, reduction of the switching frequency from growth to shortening, and reduction of the time microtubules grow. Tasidotin was studied in clinical trials phase II in patients with locally advanced or metastatic non-small cell lung carcinoma, in patients with hormone-refractory prostate cancer, and in patients with inoperable locally advanced or metastatic melanoma. However, no new results were published last 5 years. It was suggested that tasidotin is no longer being used as single or even components of multiple agents today.

Gemcabene calcium (PD 72953), the monocalcium salt of a dialkyl ether dicarboxylic acid, is a lipid-regulating compound that was first described in 1998. It down-regulates apolipoprotein C-III expression, enhancing the clearance of very low density lipoprotein (LDL), and reduces plasma triglycerides. It also raises high-density lipoprotein cholesterol (HDL). Unlike fibrates (blood trygliceride level lowering drugs), its mechanism of action is not linked to agonist or antagonist activity on PPAR-α receptors. There is limited information on the exact mechanism of action, but an anti-inflammatory profile was found, associated with a lowered expression of the high-sensitivity C-reactive protein gene regulating mechanisms. Gemcabene (administered as 6, 6’-oxybis [2, 2-dimethyl-4-hexanoic acid] monocalcium salt) has been investigated for treatment in a wide range of hyperlipidaemias, as well as atherosclerosis, and cardiovascular disorders. Gemcabene is generally well tolerated. One phase 2 study testing the preliminary efficacy and safety of gemcabene in children with established nonalcoholic fatty liver disease has been stopped early due to increasing weight and a rise in liver fat content in patients. Clinical trials are still ongoing.

Dexniguldipine (B8509-035, (-)-(R)-niguldipine) is a new dihydropyridine derivative, that exerts selective antiproliferative activity in a variety of tumor models and, in addition, has a high potency in overcoming multidrug resistance. Dexniguldipine is ( - )-(R)-enantiomer of niguldipine, of which the ( )-(S)-enantiomer shows pronounced cardiovascular hypotensive activity due to its high affinity for the voltage-dependent Ca2 channel. As compared with the (S)-enantiomer, the (R)-enantiomer has a 40-fold lower affinity for the Ca 2 channel and, accordingly, only minimal hypotensive activity in animal pharmacology models. Dexniguldipine have shown antiproliferative activity in several tumor cell lines, but the concentrations necessary to inhibit growth have varied by several orders of magnitude between cell lines. Initial results of preclinical investigations for the evaluation of the mechanism of its antiproliferative activity demonstrate that dexniguldipine interferes with intracellular signal transduction by affecting phosphoinositol pathways, protein kinase C expression, and intracellular Ca 2 metabolism. In a series of human tumor xenografts in vitro, dexniguldipine demonstrated selective antiproliferative activity against several tumor types, e.g., melanoma and renal-cell carcinoma. Striking results were obtained in a hamster model, in which neuroendocrine lung tumors could be completely eradicated by 20 weeks of oral treatment with 32.5mg/kg dexniguldipine, whereas Clara-cell-type lung tumors were not affected. In in vitro studies, dexniguldipine has been found to bind to P-glycoprotein (P-gp) and to enhance the cytotoxicity of chemotherapeutic agents such as doxorubicin and etoposide in several cell lines The synergistic effect may well be associated with the reversal of multidrug resistance (MDR) related to the activity of P-gp. In the clinical therapy of cancer, resistance to many cytostatic drugs is a major cause of treatment failure. However, the high potency of dexniguldipine (about 10-fold as compared with that of verapamil in vitro) and its low cardiovascular activity provide the opportunity to achieve blood or tumor concentrations that might be high enough to overcome Mdr 1 resistance in patients without producing dose-limiting cardiovascular effects.

Linogliride is a substituted guanidine structurally unrelated to the sulphonylureas but with a similar mechanism of action. Linogliride potentiates insulin release in isolated islets and in the perfused pancreas. In islets, linogliride is reported to stimulate insulin secretion in the presence of glucose but not in its absence. Linogliride and the sulphonylureas act via closely related mechanisms. Possible extrapancreatic effects of the agent have also been suggested. Linogliride produces hypoglycaemic effects in various non-diabetic and diabetic animals. In normal rats and dogs, it improves glucose tolerance and in fasted rats or mice, linogliride lowers blood glucose. Linogliride showed modest effects in the db/db mice but significantly lowered fasting blood glucose in neonatal streptozotocin-treated rats. Clinical studies with non-insulin-dependent diabetes patients have shown linogliride to be effective at lowering fasting and postprandial plasma glucose levels in non-insulin-dependent diabetes patients. linogliride leads to a decrease in the activity of ATP-sensitive K+ channels.

Edonentan (BMS 207940) is a highly selective biphenylsulfonamide endothelin A receptor antagonist. (11)C- and (18)F-labeled analogs of edonentan were evaluated of novel PET radioligands for imaging the endothelin-A receptor. Edonentan was in clinical trials for the treatment of heart failure however its development has been discontinued.

Fedotozine [(1R)-1-phenyl-1-[(3,4,5-trimethoxy) benzyloxymethyl]-N,N- dimethyl-n-propylamine, (2S,3S-tartrate], derived from the arylacetamide series, is an opioid drug which acts as a selective agonist for kappa(1a)-opioid receptor. Pharmacological studies have shown that fedotozine exerts a peripheral antinociceptive action, comparable with that of other kappa-agonists. Results of Phase III trials of fedotozine against irritable bowel syndrome and dyspepsia have ultimately been disappointing and was lack of efficacy in subsequent studies.

CS-834 is a beta-lactam antibiotic of a carbapenem class, developed by the Japanese company Sankyo Co. Ltd. CS-834 is an ester-type prodrug of the active metabolite R-95867. The drug showed potent and well balanced antibacterial activity as well as stability against dehydropeptidase-I. The in vivo efficacy of CS-834 was evaluated in murine systemic infections caused by 16 strains of gram-positive and -negative pathogens. The efficacy of CS-834 was in many cases superior to those of cefteram pivoxil, cefpodoxime proxetil, cefdinir, and cefditoren pivoxil, especially against infections caused by S. aureus, penicillin-resistant S. pneumoniae, E. coli, Citrobacter freundii, and Proteus vulgaris. Pharmacokinetics of CS-834 was evaluated in healthy male volunteers, but no further clinical development of the drug was reported.

Enazadrem (CP-70490-09) is an antipsoriatic agent inhibiting arachidonate 5-lipoxygenase.

Obatoclax (GX15-070) is a novel BH3 mimetic pan Bcl- 2 inhibitor. The clinically studied formulation is as obatoclax mesylate (Box 1), a salt. It is only under study as an intravenous preparation. It functions to block BH3-mediated binding of Bcl-2, Bcl-XL, Mcl-1 and A1 to Bax and Bak. Bax and Bak thus are unopposed and able to dimerize to allow initiation of intrinsic apoptosis. Preclinically, obatoclax has been shown to reverse inhibition of Bax or Bak by Bcl-2, Bcl-XL, Bcl-w and Mcl-1. Obatoclax was discovered by Gemin X, which was acquired by Cephalon, which has since been acquired by Teva Pharmaceuticals. Obatoclax had been in phase III clinical trials by Gemin X Biotechnologies (subsidiary of Teva) for the treatment of non-small lung cancer (NSCLC). The compound received orphan drug designation in the U.S. in 2004 for the treatment of chronic lymphocytic leukemia (CLL). However, Teva discontinued the development of obatoclax in 2013.

Dazopride is an antagonist of the 5-HT3 receptor and agonist of the 5-HT4 receptor, structurally related to metoclopramide. Dazopride was developed by A. H. Robins Company as an antiemetic and gastroprokinetic drug. Dazoptide demonstrated an antiemetic effect in the clinic after i.v. infusion to patients, receiving anticancer therapy.