Amonafide L-malate (AS1413, Xanafide) is a DNA intercalator and topoisomerase II inhibitor that induces apoptosis by disrupting chromatin organisation independently of ATP. This is different from classical topoisomerase II inhibitors which induce apoptosis by causing extensive DNA damage. Amonafide L-malate is also able to evade P-glycoprotein and related transporters that contribute to multi-drug resistance. AS1413 had orphan drug status in both the U.S. and the E.U. for the treatment of AML and also received Fast Track status from the U.S. FDA for the treatment of secondary AML. Amonafide L-malate was originated by Xanthus Pharmaceuticals. It was added to Antisoma's pipeline through the acquisition of Xanthus Pharmaceuticals, Inc. in June 2008. Antisoma discontinued development of Amonafide L-malate after data from the open-label, international Phase III ACCEDE trial in over 420 patients showed that 600 mg/m 2 IV amonafide for 5 days plus cytarabine missed the primary endpoint of significantly improving initial remission rate, defined as the proportion of patients who achieve CR or CRi, vs. daunorubicin plus cytarabine.

Combretastatin A4 is a vascular disrupting agent (VDA) that targets tumor vasculature to inhibit angiogenesis. Combretastatin A4 is a tubulin-binding agent that binds at or near the colchicine binding site of β-tubulin and inhibits tubulin assembly. This tubulin-binding agent was originally isolated from an African shrub, Combretum caffrum. Combretastatin A4 is cytotoxic to umbilical-vein endothelial cells (HUVECs) and to a range of cells derived from primary tumors and these cytotoxicity profiles have been used to assess several novel analogs of the drug for future development. Combretastatin A4 has antitumor activity by inhibiting AKT function. The inhibited AKT activation causes decreased cell proliferation, cell cycle arrest, and reduced in vitro migration/invasiveness and in vivo metastatic ability. Several studies in mice have shown that a single administration of combretastatin A4 (100 mg/kg) does not significantly affect primary tumor growth. However, repeated administration (12.5 – 25.0mg/kg twice daily) for periods of 10 – 20 days resulted in approximately 50% retardation of growth of ectopic Lewis lung carcinoma and substantial growth delay of T138 spontaneous murine breast tumors. In clinical studies, Combretastatin A4 has been well tolerated in patients at doses up to 56 mg/m2, following a protocol of five daily 10-minute intravenous infusions every 21 days. The disodium combretastatin A4 phosphate prodrug is currently undergoing clinical trials in the UK and USA.

Igmesine is a sigma-1 receptor agonist. It was assayed in clinical trials targeting major depressive disorder. Igmesine is the only antisecretory agent that we have tested to date that inhibits both cholera toxin and the E. coli enterotoxins. Sigma receptors are known to be present on nerves in the enteric nervous system and this would seem to be a potentially useful class of drugs to pursue for the treatment of secretory diarrhoea in humans. It was shown that when Alzheimer's disease rats were submitted to the conditioned fear stress test, igmesine can significantly reduce the stress-induced motor suppression, indicating exogenous σ-1 receptor agonists may alleviate Alzheimer's disease-associated depressive symptoms.

Pardoprunox is a partial D2/3 dopamine receptor agonist and full 5-HT1A serotonin receptor agonist. Partial D(2/3) dopamine (DA) receptor agonists provide a novel approach to the treatment of the motor symptoms of Parkinson's disease that may avoid common dopaminergic side effects, including dyskinesia and psychosis. Pardoprunox passed phase III clinical trial for the treatment of Parkinson's disease.

Gaboxadol (or THIP) is a direct GABA mimetic ligand at delta-containing receptors. Gaboxadol went into human clinical trials to test if the drug promoted sleep. It was generally well tolerated. Gaboxadol enhances delta power in NREM sleep in humans. Gaboxadol failed in Phase III for sleep studies. The side effects of Gaboxadol have been described as mild and similar in quality to those of other GABA-mimetics. Gaboxadol is in development with Ovid Therapeutics as a treatment for Angelman syndrome, fragile X syndrome and epilepsy.

Eprodisate (1,3-propanedisulfonate) is a negatively charged, sulfonated molecule of low molecular weight that has structural similarities to heparin sulfate; it is a glycosaminoglycan mimetic that binds to the glycosaminoglycan (GAG) binding site on serum A amyloid (AA) to prevent its interaction with glycosaminoglycan and arrest amyloidosis, or inhibit amyloid deposition. In nonclinical toxicity studies in two animal species (i.e., rat and dog), eprodisate was administered orally at doses of up to 2000 mg/kg/day for 39 weeks: eprodisate showed low toxicity potential at doses several fold higher than the anticipated clinical dose, was well tolerated upon chronic exposure and was found to be nonmutagenic and nonclastogenic. Furthermore, a series of safety pharmacology studies showed that eprodisate does not have any clinically significant effect on major organ function.

Pafuramidine or DB289, [2,5-bis-(4-amidinophenyl)furan bis-O-methylamidoxime] is a pro-drug of DB75, [2,5-bis(4-amidinophenyl)furan] also known as furamidine. The biotransformation process of DB289 to DB75 in the human liver consists of three O-demethylation reactions catalyzed by the Cyp4F enzyme subfamily and three N-dehydroxylation reactions catalyzed by cytrochrome b5 and NADH-cytochrome b5 reductase. DB289 was studied for therapeutic treatment against human African trypanosomiasis, Pneumocystis pneumonia and malaria. In November 2006, Immtech Pharmaceuticals, Inc. announced that the U.S. Food and Drug Administration (FDA) had granted orphan drug designation for pafuramidine (DB289) to treat Pneumocystis jiroveci pneumonia (PCP), a common life-threatening opportunistic infection in HIV/AIDS and other immunosuppressed patients. Despite the high efficacy of DB289 in patients, the mechanism of action of DB75 is unknown. The mechanism of antimicrobial activity of diamidine compounds is incompletely understood. They undergo active uptake by purine transporter systems in trypanosomes and their mechanism of action may involve interference with DNA-associated enzymes inhibition of heme crystallization11 or/and collapse of the transmitochondrial membrane potential.

Otenabant (CP-945,598) is Pfizer developed as a potent and selective cannabinoid receptor CB1 antagonist with Ki of 0.7 nM, which exhibits 10,000-fold greater selectivity against human CB2 receptor, for treatment of obesity. In clinical trial III Pfizer decided to discontinue the development program based on changing regulatory perspectives on the risk/benefit profile of the CB1 class and likely new regulatory requirements for approval.

Rapastinel (formerly known as GLYX-13) is an investigational intravenous formulation of a novel NMDA receptor partial agonist, which is being evaluated for adjunctive treatment of Major depressive disorder, and has shown a rapid onset of antidepressant efficacy 1 day after a single dose in a Phase 2 clinical trial of patients with Major depressive disorder who had an inadequate response to one or more antidepressants. No psychotomimetic or hallucinogenic side effects were observed with rapastinel. Few adverse events were reported by 5% or more of subjects and these were rated as mild or moderate. These included headache, somnolence, dizziness, dysgeusia, and fatigue. On January 29, 2016, Allergan (who acquired Naurex in July 2015) announced that rapastinel had received Breakthrough Therapy designation from the U.S. FDA for adjunctive treatment of major depressive disorder.

Gaboxadol (or THIP) is a direct GABA mimetic ligand at delta-containing receptors. Gaboxadol went into human clinical trials to test if the drug promoted sleep. It was generally well tolerated. Gaboxadol enhances delta power in NREM sleep in humans. Gaboxadol failed in Phase III for sleep studies. The side effects of Gaboxadol have been described as mild and similar in quality to those of other GABA-mimetics. Gaboxadol is in development with Ovid Therapeutics as a treatment for Angelman syndrome, fragile X syndrome and epilepsy.