Nolpitantium (SR-140333) is a highly selective nonpeptide antagonist of neurokinin-1 (NK1) receptor. Nolpitantium potently, selectively and competitively inhibited substance P binding to NK1 receptors from various animal species, including humans. In vitro, it was a potent antagonist in functional assays for NK1 receptors such as [Sar9, Met(O2)11]substance P-induced endothelium-dependent relaxation of rabbit pulmonary artery and contraction of guinea-pig ileum. Up to 1 mkM, Nolpitantium had no effect in bioassays for NK2 and NK3 receptors. The antagonism exerted by Nolpitantium toward NK1 receptors was apparently non-competitive, with pD2' values between 9.65 and 10.16 in the different assays. Nolpitantium also blocked in vitro [Sar9, Met(O2)11]substance P-induced release of acetylcholine from rat striatum. In vivo, Nolpitantium exerted highly potent antagonism toward [Sar9, Met(O2)11]substance P-induced hypotension in dogs, bronchoconstriction in guinea-pig) and plasma extravasation in rats. Nolpitantium was found to be effective in the modulation of the inflammatory response and airway remodeling in mice. Nolpitantium is reported to cause antagonism of the SP-induced relaxations of human isolated intralobar pulmonary arterial rings. Nolpitantium also blocked the activation of rat thalamic neurons after nociceptive stimulation. Nolpitantium has been shown to reduce the severity of inflammation in trinitrobenzene sulfonic acid-induced colitis in the rat colon. Nolpitantium inhibited mustard oil-induced plasma protein extravasations in the dorsal skin of the rat hind paw. Nolpitantium had been in some phase II clinical trials but further studies were discontinued.

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.

Millennium (a wholly-owned subsidiary of Takeda) was developing TAK- 901 for the treatment of cancer. TAK-901 is an inhibitor of Aurora A/B with IC50 of 21 nM/15 nM. It is not a potent inhibitor of cellular JAK2, c-Src or Abl. TAK-901 is in phase I clinical trials by Millennium Pharmaceuticals for the treatment of advanced hematological malignancies. TAK-901 had been in phase I clinical trials for solid tumors. However, this study was discontinued.

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.

Brovanexine is a derivative of bromhexine used as an adjunct to antibacterials in preparations for the treatment of respiratory-tract infections. Oral administration of brovanexine hydrochloride (BR-222) caused a significant increase in the output volume of respiratory tract fluid. Brovanexine at 10 and 20 mg/kg showed a tendency to reduce the viscosity of respiratory tract fluid in anesthetized dogs. Brovanexine also showed a tendency to reduce the viscosity of sputum obtained from the SO2-exposed rabbits.

Deferitazole is an iron chelator, developed by the FerroKin BioSciences (later acquired by Shire, and then by Takeda). Deferitazole is a member of the desazadesferrithiocin class of siderophore-related tridentate chelators. It binds Fe(III) with very high affinity and selectivity over Fe(II) and other biologically important metals. Deferitazole was investigated in phase 2 clinical trials in patients with iron overload due to repeated red blood cell transfusion and beta-thalassemia, however, the development of the drug was discontinued. In preclinical models, deferitazole demonstrated efficacy for the treatment and prevention of malaria.

Ezatiostat (TLK199) [γ-glutamyl-S-(benzyl)cysteinyl-R-phenyl glycine diethyl ester] is an inhibitor of Glutathione S-transferase P1–1 (GSTπ). The drug is a peptidomimetic of GSH (glutathione), esterified to enhance cellular uptake and designed to bind to the “G-site” of GSTP1–1. Independent of catalysis inhibition, TLK199 also disrupts the protein:protein interaction site(s) between GSTP1–1 and JNK1. Telik Inc was developing TLK-199 for the potential prevention of myelosuppression in blood diseases, namely myelodysplastic syndrome.

Adaprolol is a beta-adrenergic antagonist that is being developed as a topical agent to treat glaucoma. Adaprolol demonstrated a safer cardiovascular profile, especially in the population over 70 years old. It was in Phase II clinical trials for the treatment of glaucoma. This research has been discontinued.

Talopram (Lu 3-010) is a selective inhibitor norepinephrine transporter belonging to the antidepressants of the thymoleptic group.

Clodazon (AW 142446) is an antidepressant drug investigated in Germany in the 1960s. In animal models, clodazon inhibits the catalepsy induced by tetrabenazine and it potentiates the effect of catecholamines, both effects being of the order experienced with imipramine. In clinical trials, about 2/3 of the patients showed a positive antidepressive effect with few side effects.