GV 150526A (gavestinel) is an investigational drug for a neuroprotective therapy of acute ischemic stroke within 6 hours of symptom onset. It is a potent and selective non-competitive antagonist at the glycine site of the N-methyl-D-aspartate receptor (NMDA) which reduces infarct volume in experimental stroke models. Gavestinel acts at the strychnine-insensitive glycine binding site of the NMDA receptor-channel complex with nanomolar affinity (pKi = 8.5), coupled with high glutamate receptor selectivity. Gavestinel displays higher than 1000-fold selectivity over NMDA, AMPA and kainate binding sites and is orally bioavailable and active in vivo. GV 150526A inhibited convulsions induced by NMDA in mice, when administered by both IV and po routes (ED50 = 0.06 and 6 mg/kg, respectively). The safety and efficacy of GV150526 were studied in two phase III randomized placebo-controlled clinical trials of acute ischemic stroke patients within 6 h from onset [The Glycine Antagonist in Neuroprotection (GAIN) International and GAIN Americas Trials] sponsored by GlaxoSmithKline. The results of these trials suggested that gavestinel was not of substantial benefit or harm to patients with primary intracerebral hemorrhage.

Retaspimycin (IPI-504) was previously under development by manufacturer Infinity Pharmaceuticals in conjunction with MedImmune, a part of AstraZeneca. Retaspimycin is a small-molecule inhibitor of heat shock protein 90 (HSP90) with antiproliferative and antineoplastic activities. Retaspimycin binds to and inhibits the cytosolic chaperone functions of HSP90, which maintains the stability and functional shape of many oncogenic signaling proteins and may be overexpressed or overactive in tumor cells. Retaspimycin-mediated inhibition of HSP90 promotes the proteasomal degradation of oncogenic signaling proteins in susceptible tumor cell populations, which may result in the induction of apoptosis. Orphan drug designation was assigned to the compound by the FDA for the treatment of gastrointestinal stromal cancer (GIST). Infinity Pharmaceuticals has discontinued the development of retaspimycin (IPI-504) an inhibitor of the HSP-90) complex, for the treatment of cancer due to lack of efficacy in 1913.

Asimadoline is an orally active, highly selective kappa-opioid receptor agonist with approximately 500-fold greater affinity for human kappa-, as compared with either delta- or mu-opioid receptors. Due to its high selectivity for the kappa-opioid receptor, asimadoline does not produce mu-opioid like side effects. It is investigated for use/treatment in irritable bowel syndrome, pruritus, postoperative ileus. A drug interaction study investigating the coadministration of asimadoline with ketoconazole was performed in healthy volunteers - a two to three-fold increase in AUC and Cmax of asimadoline was observed with concomitant administration of ketoconazole. The most common adverse events are diarrhea, nausea, sinusitis, headache and fatigue.

Remacemide is a low-affinity noncompetitive NMDA receptor antagonist with sodium channel blocking properties. It has been studied for a number of conditions including acute ischemic stroke, epilepsy, Parkinsons Disease, and Huntington's disease. It was concluded, that was unlikely that remacemide would be further developed as an antiepileptic drug. As for other conditions, there no any information in the literature, why remacemide is no longer being developed for them.

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.

Otamixaban is a synthetically derived parenteral fXa inhibitor currently in late stage clinical development at Sanofi-Aventis for the management of acute coronary syndrome. Otamixaban is a potent (Ki = 0.5 nM), selective, rapid acting, competitive and reversible fXa inhibitor that effectively inhibits both free and prothrombinase-bound fXa. Factor Xa (fXa) is a critical serine protease situated at the confluence of the intrinsic and extrinsic pathways of the blood coagulation cascade. FXa catalyzes the conversion of prothrombin to thrombin via the prothrombinase complex. Its singular role in thrombin generation, coupled with its potentiating effects on clot formation render it an attractive target for therapeutic intervention. In vivo experiments have demonstrated that Otamixaban is highly efficacious in rodent, canine and porcine models of thrombosis. In addition, recent clinical findings indicate that Otamixaban is efficacious, safe and well tolerated in humans and therefore has considerable potential for the treatment of acute coronary syndrome. Following the results of the Treatment of non-ST elevation Acute coronary syndrome with otamixaban, Sanofi has decided to discontinue the investigational programme with otamixaban, due to efficacy lower than expected. Otamixaban did not show superior benefit/risk to the combination of unfractionated heparin.

Dovitinib is an orally active small molecule that exhibits potent inhibitory activity against multiple receptor tyrosine kinases (RTK) involved in tumor growth and angiogenesis. Dovitinib strongly binds to fibroblast growth factor receptor 3 (FGFR3) and inhibits its phosphorylation, which may result in the inhibition of tumor cell proliferation and the induction of tumor cell death. In addition, this agent may inhibit other members of the RTK superfamily, including the vascular endothelial growth factor receptor; fibroblast growth factor receptor 1; platelet-derived growth factor receptor type 3; FMS-like tyrosine kinase 3; stem cell factor receptor (c-KIT); and colony-stimulating factor receptor 1; this may result in an additional reduction in cellular proliferation and angiogenesis, and the induction of tumor cell apoptosis. There are several ongoing Phase I/III clinical trials for dovitinib.

Fosmidomycin (3-(formylhydroxyamino)-propylphosphonic acid mono-sodium salt, 3-(N-formyl-N-hydroxyamino)-propylphosphonic acid mono-sodium salt, FR-31564) is a potent inhibitor of P. falciparum 1-deoxy-D-xylulose-5-phosphate reductoisomerase (PfDXR), developed by Albert Schweitzer Hospital for P. falciparum malaria treatment. Fosmidomycin was originally isolated as natural antibiotic from Streptomyces lavendulae. Fosmidomycin is active against a broad range of enterobacteria, but not against Gram-positive organisms or anaerobes. Fosmidomycin was developed as far as an early phase II study for the treatment of urinary tract infections by Fujisawa Pharmaceutical Company (Osaka, Japan) in the early eighties, but these trials have been discontinued. In recent clinical studies, it was shown that fosmidomycin is effective in curing uncomplicated Plasmodium falciparum malaria in humans. The treatment was well tolerated and resulted in a fast parasite and fever clearance. However, the high rate of recrudescence precludes the use of fosmidomycin as a monotherapy. In drug combination studies, the synergy of fosmidomycin with clindamycin was observed. Clinical studies with a fosmidomycin-clindamycin combination are currently ongoing.

Vercirnon (GSK-1605786, CCX-282, nTraficet-EN) is a selective, and potent antagonist of human CCR9. Vercirnon binds to the intracellular side of the receptor, exerting allosteric antagonism and preventing G-protein coupling. CCR9 is a tissue-specific lymphocyte trafficking molecule that selectively attracts both B- and T-cells to the small gut. Inhibition of CCR9 by GSK-1605786 may inhibit B- and T-cell entry to the small gut and ameliorate inflammation while leaving immune function at other anatomical sites unaffected. Vercirnon is an orally bioavailable, anti-inflammatory agent that is being developed by ChemoCentryx for treatment of inflammatory bowel disease with an initial focus in Crohn's disease. A pivotal phase III programme of vercirnon was initiated in patients with moderate-to-severe Crohn's disease, however, the programme was suspended when the first pivotal trial failed to meet its primary endpoint. Phase II trials for ulcerative colitis and celiac disease were conducted, however investigations for ulcerative colitis were suspended while no further development has been reported for celiac disease.

Enclomiphene (Androxal), in development by Repros Therapeutics Inc, is a non-steroidal estrogen receptor antagonist that promotes gonadotropin-dependent testosterone secretion by the testes. Enclomiphene constitutes the trans-stereoisomer of clomiphene citrate, a drug that has been widely prescribed for several decades for the treatment of female ovulatory dysfunction. Because of the antagonistic effects of enclomiphene, the drug has the potential to increase serum testosterone levels in men with secondary hypogonadism by restoring physiological endogenous testosterone secretion while maintaining testicular volume and, potentially, spermatogenesis. In clinical trials conducted to date, enclomiphene demonstrated significant efficacy in the physiological restoration of testosterone levels in males with secondary hypogonadism. The compound also exhibited an unanticipated favorable effect on fasting plasma glucose; this result has been accompanied by rapidly accumulating evidence from other researchers for a bidirectional relationship between low serum testosterone and obesity/metabolic syndrome (syndrome X) in men.