Talaglumetad (also known as LY-544344) is a bicyclohexane derivative patented by Eli Lilly and Company as modulators of metabotropic glutamate receptor. Talaglumetad acts as a prodrug of Eglumegad, a selective agonist of metabotropic glutamate receptors (mGluR2/3) and metabolized to release active compound by both human jejunal homogenates and rat liver homogenates. In experiments on mice, Talaglumetad was found to be as effective as diazepam for treating anxiety symptoms in several standard tests, but without producing any of the negative side effects of diazepam such as sedation and memory impairment.

Nemifitide is a peptide analog of melanocyte-inhibiting factor (MIF) that has been reported to relieve depressive symptoms in a very short period. Tetragenex (formerly Innapharma) was developing nemifitide with potential in the treatment of depression. Clinical data obtained from two pilot clinical studies, double-blind, placebo-controlled, parallel-design, in-patient and outpatient, suggested that nemifitide may have the following advantages over current therapies: rapid onset of action (3–5 d), short period of administration (5–10 doses over a 1–2 wk period), and a relatively long duration of treatment effect (3–6 months). The mechanism of action of nemifitide was investigated by evaluating its in-vitro receptor binding and in-vivo localization in the rat brain as well as its interactions with psychoprobes indicative of specific neurotransmitter pathways in acute studies in rats. The results of these studies indicate that nemifitide readily crosses the blood–brain barrier and is localized mainly in the amygdala, hippocampus and frontal cortex of the rat brain. Its in-vitro binding to several receptors including 5-HT-2A, as well as its significant interaction with d-fenfluramine in the rat, suggest the participation of the serotonergic pathway in its mode of action in a different way than that observed with SSRI antidepressants.

Droxinavir is hydroxyethylurea human immunodeficiency virus type 1 (HIV-1) protease inhibitor. Position 88 of HIV-1 protease gene plays a key role in the interaction between droxinavir and the protease molecule. A mutation in this position, located outside the active site, confers resistance to the hydroxyethylurea inhibitor droxinavir. The V82A and N88S substitutions conferred droxinavir resistance on HIV-1 recombinant variants. Positions 82 and 88 are reported to be variable in natural populations isolated from patients who have not been treated with protease inhibitors. Droxinavir had been in preclinical phase for the treatment of HIV-1 infection. However, this study was discontinued.

Managlinat dialanetil (MB06322 or CS-917) is an inhibitor of fructose 1,6-bisphphosphatase. Managlinat dialanetil is a bisamidate prodrug and its activation requires a two-step enzyme catalyzed reaction. Metabasis Therapeutics Inc in collaboration with Daiichi Sankyo Co Ltd was developing managlinat dialanetil for the potential treatment of type 2 diabetes.

Valategrast (R-411) is a dual-acting α4/β1 - α4/β7 integrin antagonist which underwent clinical development with Roche for the treatment of multiple sclerosis (MS) and asthma. Phase I and II studies have been conducted. It had shown good efficacy in animal disease models. Following oral administration, R-411 was rapidly and completely biotransformed into its active metabolite, RO-0270608, most of which was eliminated by biliary excretion. R-411 had shown acceptable pharmacokinetics and good safety in healthy volunteers. R-411 inhibited eosinophil and T H 2 cell excitation and survival, and inhibited eosinophil migration from blood to pulmonary tissues. The idea of combining R-411 with montelukast (leukotriene antagonist) in the pharmaceutical dosage forms, therefore, provided a therapeutic treatment that had the combined effect of reducing circulating eosinophil counts and reducing eosinophil egress into pulmonary tissues, thereby providing an early onset of bronchodilation as well as sustained anti-inflammatory effects. Valategrast had been in phase II clinical trials by Roche for the treatment of asthma and in phase I clinical trials for the treatment of multiple sclerosis (MS). However, the study had been discontinued. Development of Valategrast was discontinued for the treatment of asthma after clarification of the regulatory framework for that class of compounds.

LAMIFIBAN is a potent and selective nonpeptide glycoprotein IIb/IIIa antagonist. It inhibits platelet aggregation and thrombus formation by preventing the binding of fibrinogen to platelets. It was in clinical development as an injectable antithrombotic agent for treating and preventing acute coronary syndromes but showed no significant effects on clinical outcomes.

Canfosfamide is a modified glutathione analogue and nitrogen mustard prodrug, with potential antineoplastic activity. Canfosfamide is selectively activated by glutathione S-transferase P1-1 an enzyme that is over-expressed in many human cancers including ovarian cancer. GST P1-1-mediated cleavage leads to an active cytotoxic phosphorodiamidate alkylating metabolite that forms covalent linkages with nucleophilic centers in tumor cell DNA, which may induce a cellular stress response and cytotoxicity, and decrease tumor cell proliferation. Preclinical studies showed that canfosfamide inhibited the growth and was cytotoxic to a wide range of established cancer cell lines including those derived from ovarian cancer (OVCAR3, HEY, SK-OV-3). Canfosfamide treatment inhibited cancer cell proliferation and induced apoptosis through the activation of the cellular stress response kinase pathway. The cytotoxic activity of canfosfamide correlated with the expression of GST P1-1. Cancer cells in which GST expression levels were increased by transfection with the GST P1-1 gene, were more sensitive to the cytotoxic effects of canfosfamide than the parental cell lines Canfosfamide in combination with pegylated liposomal doxorubicin is well tolerated and active in platinum and paclitaxel refractory or resistant ovarian cancer.

Puromycin dihydrochloride belongs to the aminonucleoside family of antibiotics and is isolated from Streptomyces alboniger. Since the partial structure of this antibiotic showed it to be a purine derivative, puromycin was assigned as its generic name. Puromycin is a broad spectrum antibiotic and antibacterial agent. It is active against Gram-positive microorganisms, less active against acid-fast bacilli, and weakly active against Gram-negative microorganisms. It acts very quickly and can kill 99% of the cells within 2 days. It also exhibits antitumor activity in studies on brain tumor cells. Puromycin is a protein synthesis inhibitor that causes premature chain termination by acting as an analog of the 3’-terminal end of aminoacyl-tRNA. It has been used to study transcriptional regulatory mechanisms that control the sequential and coordinate expression of genes during cell differentiation.

Davalintide (AC-2307) is a second-generation mimetic of a pancreatic peptide hormone amylin, developed by Amylin Pharmaceuticals. In preclinical models, davalintide possessed enhanced pharmacological properties and was able to reduce food intake. Safety, tolerability, and effect on body weight of subcutaneous davalintide were investigated in obese or overweight subjects. The results of the clinical trial were not reported, but Amylin decided to discontinue davalintide in 2010.