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.

Liarozole is an imidazole-containing compound that inhibits the cytochrome P-450-dependent metabolism of all-trans-retinoic acid (RA). Liarozole, a retinoic acid (RA) metabolism-blocking agent (RAMBA) in clinical development, has been granted orphan drug designation for congenital ichthyosis by the European Commission and the U.S. Food and Drug Administration. Later, based on the mixed results from a phase II/III trial of liarozole for the treatment of ichthyosis, Barrier decided to discontinue the development of liarozole. Liarozole displays antitumor activity against androgen-dependent and independent rat prostate carcinomas.A large phase III international study was completed comparing liarozole 300 mg twice daily with cyproterone acetate (CPA) 100 mg twice daily in a total of 321 patients with metastatic prostate cancer in relapse after first-line endocrine therapy. The results indicate that liarozole might be a possible treatment option for prostate cancer (PCA) following failure of first-line endocrine therapy.

CGC-11047 is a polyamine analog designed to halt cell growth and induce apoptosis of cancer cells. In preclinical models CGC-11047 significantly inhibited tumor development in both lung and prostate cancer models when administered as a single agent. In the lung cancer model, CGC-11047 potentiated the antitumor effect of cisplatin. Although potent activity was observed with CGC-11047 and bevacizumab when administered as single agents in the prostate cancer model, the combination arm significantly enhanced antitumor activity compared with either agent alone. In all experiments, CGC-11047 was well tolerated with no adverse effects on bodyweight gain.

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.

Quinpirole (LY 171,555) is a psychoactive drug and research chemical which acts as a selective D2 and D3 receptor agonist. Quinpirole is the most widely used D2 agonist in in vivo and in vitro studies. Specific quinpirole binding in rat brain was saturable, and dependent on temperature, membrane concentration, sodium concentration and guanine nucleotides. Saturation analysis revealed high affinity binding characteristics (KD = 2.3 nM) which were confirmed by association-dissociation kinetics. The regional distribution of [3H]quinpirole binding sites roughly paralleled the distribution of [3H]spiperone binding sites, with greatest densities present in the striatum, nucleus accumbens and olfactory tubercles. A variety of drugs, most notably monoamine oxidase inhibitors (MAOls), inhibit the binding of [3H]quinpirole, but not [3H]spiperone or [3H](-)N-n-Propylnorapomorphine, in rat striatal membranes by a mechanism that does not appear to involve the enzymatic activity of MAO. Clinically antidepressant MAOIs exhibited selectivity between sites labeled by [3H]quinpirole and [3H]spiperone as did a number of structurally related propargylamines and N-acylethylenediamine derivatives and other drugs such as debrisoquin and phenylbiguanide. Quinpirole has been shown to increase locomotion and sniffing behavior in mice and induces compulsive behavior symptomatic of obsessive compulsive disorder in rats.

Emilium is an antiarrhythmic agent and cardiac depressant.

Captamine is ethanethiol derivative that has been studied as the chelating and radioprotective agent. Captamine, a potent duodenal ulcerogenic, stimulates gastric acid and gastrin secretion and decreases immunoreactive somatostatin (IRS) from the gut and hypothalamus of the rat.

m-Chlorophenylpiperazine (meta-chlorophenylpiperazine or mCPP) is a psychoactive substance, which is illegal in many countries but can be found on the black market. It induces endocrine, neurological and psychiatric effects. mCPP is a partial agonist at the 5-HT2C receptor but antagonized the 5-HT2B and 5-HT3 receptors. mCPP is also an active metabolite of the drug trazodone, which is used as an effective antidepressant drug with a broad therapeutic spectrum, including anxiolytic efficacy. It is known, that mCPP induces migraine attacks and that the decrease of food intake induced by the mCPP depends on its ability to act as a serotonin agonist is a brain.

Fenobam is a selective and potent metabotropic glutamate (mGlu)5 receptor antagonist with inverse agonist activity. Fenobam was previously investigated as an anxiolytic in a number of phase II studies in the early 1980s. These studies revealed a mixed picture of anxiolytic efficacy, with double blind, placebo controlled trials variously reporting the compound as active or inactive. This discrepancy was not easily reconciled based on patient numbers, dose level, duration of treatment, or outcome measures. The positive effects seen in animal models of fragile X syndrome (FXS) treated with fenobam or other mGluR5 antagonists, the apparent lack of clinically significant adverse effects, and the potential beneficial clinical effects seen in this pilot trial support further study of the compound in adults with FXS.

Doxpicomine is the hydrochloride salt of l-3[(dimethylamino)-(m-dioxan-5-yl)methyl]pyridine, a derivative of substituted 1,3 dioxanes. Its analgesic effect appears to be mediated centrally through opiate-like receptors. Preclinical animal studies revealed analgesic activity and duration of action of the same order as that of meperidine and codeine when administered subcutaneously and of codeine but of shorter duration when administered orally. The analgesic effects were reversed by naloxone. The drug did not reduce or antagonize the analgesic effect of morphine. Drowsiness is an expected response to effective analgesics. It was the foremost side effect observed but was of short duration and minimal intensity and did not interfere with the postoperative regimen of coughing, deep breathing, and early ambulation. Nausea and vomiting were not reported after doxpicomine.