Clazosentan is an endothelin receptor antagonist, developed by the Swiss pharmaceutical company Actelion, and licensed to its spin-off, Idorsia. The drug was designed to inhibit endothelin-mediated cerebral vasospasm and associated delayed ischaemic neurological deficit. The drug has been investigated in a phase III clinical trials in patients with aneurysmal subarachnoid hemorrhage. Clazosentan at 5 mg/h had no significant effect on mortality and vasospasm-related morbidity or functional outcome. Clinical investigation of a higher dose of the drug is underway.

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.

2,2-DIMETHYLBUTYRIC ACID (HQK-1001) is an orally administered SCFAD (Short Chain Fatty Acid Derivative), which has shown an excellent safety profile and biologic effects on fetal hemoglobin induction and red blood cell production in the laboratory, relevant animal models, and in clinical trials carried out in healthy human subjects as well as patients with sickle cell disease and beta thalassemia. The compound has received Orphan Drug Designation in the United States and Europe for both sickle cell disease and beta thalassemia. HemaQuest Pharmaceuticals was developing HQK-1001 for the oral treatment of sickle cell anaemia and beta thalassaemia. HQK-1001 has been evaluated in phase II trials for beta thalassaemia and sickle cell anaemia.

Denufosol is a novel second-generation, metabolically stable, selective P2Y(2) receptor agonist. As ion channel regulator denufosol corrects the ion transport defect and increases the overall mucociliary clearance in cystic fibrosis (CF) lung disease by increasing chloride secretion, inhibiting sodium absorption, and increasing ciliary beat frequency in the airway epithelium independently of cystic fibrosis transmembrane conductance regulator genotype. Denufosol improved lung function relative to placebo in cystic fibrosis patients with normal to mildly impaired lung function. The drug half-life is 25 hours in ex vivo CF sputum and 3 hours when added in vitro to human respiratory epithelial cultures. Denufosol has been generally well-tolerated in healthy volunteers and patients with cystic fibrosis. The most common adverse events were in the respiratory system, with cough having the highest frequency.

Tretazicar is a dinitrobenzamide prodrug that is converted in the presence of the enzyme NQO2 and co-substrate caricotamide (EP-0152R) into a potent cytotoxic bifunctional alkylating agent. Tretazicar is a product that belongs to a family of products used in the treatment of cancer because of its capacity to kill cells. The enzyme that activates tretazicar is present in leishmania cells where the product can be transformed and be active. Tretazicar kills infected cells by binding to the genetic material (DNA) of the cells and creating bonds that disrupt the genetic material and its function, finally resulting in the death of the infected cell. On 4 February 2008, orphan designation EU/3/08/529 was granted by the European Commission to Morvus Technology Limited, United Kingdom, for tretazicar for the treatment of visceral leishmaniasis. On 4 February 2008, orphan designation EU/3/08/529 was granted by the European Commission to Morvus Technology Limited, United Kingdom, for tretazicar for the treatment of visceral leishmaniasis. Tretazicar had been in phase II clinical trial for the treatment of liver cancer. However, this development was discontinued.

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.

Evofosfamide, also formerly known as TH-302, is an investigational hypoxia-activated prodrug and is used to target cancerous cells under hypoxic conditions, which is a feature possessed by multiple solid tumors including glioblastoma and pancreatic cancer. Within regions of tumor hypoxia, evofosfamide releases bromo isophosphoramide mustard (Br-IPM), a potent DNA alkylating agent that kills tumor cells by forming DNA crosslinks. Once activated in hypoxic tissues, Br-IPM can also diffuse into surrounding oxygenated regions of the tumor and kill cells there via a “bystander effect”. Because of its preferential activation in the targeted hypoxic regions of solid tumors, evofosfamide may be less likely to produce broad systemic toxicity seen with untargeted cytotoxic chemotherapies.

Pridopidine is an experimental drug candidate belonging to a class of agents known as dopidines, which act as dopaminergic stabilizers in the central nervous system. As a dopamine stabilizer, pridopidine is thought to reduce the effects of dopamine when there’s too much and increase its effects when there’s too little. Pridopidine, therefore, plays two opposing roles in the brain, which stabilize dopamine levels. In this way, pridopidine is thought to help the brain reestablish a normal balance of neurotransmitters, and thus regain control over motion. Pridopidine intended to treat Huntington’s disease movement symptoms. Pridopidine was well tolerated and had an adverse event profile similar to a placebo.

Troxacitabine is a synthetic nucleoside analogue. It is a poor substrate for nucleoside transporters and gains entry into cells by passive diffusion. Intracellular conversion to its active triphosphate form is via deoxycytidine kinase. Incorporation of this metabolite into DNA results in immediate chain termination and apoptosis induction. It is the first nucleoside analog with anticancer activity that has an unnatural stereochemical configuration. The dose-limiting adverse reactions were stomatitis and hand–foot syndrome.

Ibutamoren (L-163,191 MK-0677) is a spiropiperidine agonist of the ghrelin receptor and a growth hormone secretagogue. Ibutamoren mimics the actions of growth hormone releasing peptide-6 to increase serum levels of serum insulin-like growth factor-I (IGF-I). Orally active Ibutamoren was being developed by Merck & Co. for a variety of indications, including fibromyalgia, muscle wasting/weakness in patients with chronic kidney disease, Alzheimer's disease and fractures.However, there has been no recent development reported or development has been discontinued for these indications.