The novel compounds clamikalant (HMR 1883) or its sodium salt HMR 1098) have been shown to block selectively Kir6.2/SUR1-composed K(ATP) channels. Clamikalant is under development by Aventis Pharma (formerly Hoechst Marion Roussel) for the potential treatment of heart arrest and ventricular arrhythmias. Nevertheless, clamikalant and its sodium salt did not pass the clinical trials

Nafoxidine is a nonsteroidal antiestrogen available as an investigational agent from the Investigational Drug Branch of the National Cancer Institute. It has been used effectively in the treatment of breast cancer patients. Nafoxidine competes with endogenous estrogen for binding to specific estrogen receptors. This agent also inhibits angiogenesis in some tissues by blocking the effects of fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF); paradoxically, it may enhance angiogenesis in uterine tissue. Nafoxidine also induces oxidative stress, protein kinase C and calcium signaling.

Darusentan is an orally active, propanoic acid-based endothelin receptor antagonist (ERA) that selectively blocks endothelin-1 (ET-1) binding to the endothelin type-A (ETA) receptor. Darusentan exhibited subnanomolar binding affinity and approximately 1000-fold selectivity for the ETA receptor in binding experiments conducted in vitro under steady-state conditions. Darusentan is orally bioavailable and, when administered to humans, maximum plasma concentrations are observed within 1–2 h post dosing. The mean elimination half-life is relatively long (>15 h), which is consistent with once-daily dosing. Darusentan is primarily glucuronidated by Phase II enzymes in the liver, and the major route of elimination of Darusentan and its metabolites is via the bile. Some glucuronidated metabolites of Darusentan are also excreted in the urine. Darusentan doses up to 300 mg/day were well tolerated and associated with a manageable safety profile in patients with resistant hypertension (RHTN). The most frequently reported adverse events in Ddarusentan-treated subjects were peripheral edema (17%) and headache (11%), which were mostly mild or moderate in severity. Other commonly reported adverse events in the Darusentan treatment group were sinusitis (8%), dizziness (7%), upper respiratory tract infection (5%) and gastroenteritis (5%). In phase III clinical trial the mean reductions in clinic systolic and diastolic blood pressures were 9/5 mm Hg with placebo, 17/10 mm Hg with Darusentan 50 mg, 18/10 mm Hg with Darusentan 100 mg, and 18/11 mm Hg with Darusentan 300 mg. Unfortunately, phase III clinical trial evaluating Darusentan did not achieve its co-primary efficacy endpoints of achieving a change in systolic and diastolic blood pressure after 14 weeks compared to a placebo. Perhaps for this reason, shortly after the top-line results of this study became known, the sponsor announced that Darusentan would not be developed further for resistant hypertension.

Glemanserin is a selective antagonist of the 5-HT2A receptor. It was tested in a clinical trial, in patients with generalized anxiety disorder, however, it did not demonstrate significant anxiolytic effects.

Sonepiprazole exhibits highly specific binding to the D4 dopamine receptor with more than 100-fold selectivity for the D4 receptor over other receptors, including dopamine, serotonin, and adrenergic receptors. It is a neutral antagonist at the D4 dopamine receptor and is devoid of dopamine agonist activity. Sonepiprazole selectively induces c-fos expression in the prefrontal cortex and blocks behavioral, biochemical, and genomic effects of repeated amphetamine administration in rats. Sonepiprazole was investigated as an antipsychotic for the treatment of schizophrenia in a placebo-controlled clinical trial, but in contrast to its comparator olanzapine no benefits were found and it was not researched further for this indication.

Ocaperidone [R 79598] is an equipotent antagonist of central dopamine D2 and serotonin2 receptors being investigated as a potential antipsychotic agent. Ocaperidone is a benzisoxazol piperidine antipsychotic primarily binds and with high affinity to 5-HT2 (serotonin) receptors, alpha1 and alpha 2 adrenergic receptors, dopamine D2 receptors and histamine H1 receptors. Ocaperidone is an antagonist primarily at the 5HT and D2 receptors. A proposed mechanism of action is the central D2 receptor blockade which is common to all neuroleptics that are used to treat positive symptoms of schizophrenia.

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.

Metiamide is an antagonist of histamine H2-receptors synthesized at Smith Kline & French Laboratories. It potently inhibited gastric acid secretion. Metiamide demonstrated promising clinical effects in patients with duodenal ulcers but questionable safety.

Tioxaprofen is a sulfidopeptide leukotriene receptor antagonist. It is an orally bioavailable anti-inflammatory agent, originated by Kyorin Pharmaceutical, which is being developed in clinical trials by the US company MediciNova for the treatment of interstitial cystitis and asthma. The actions of the drug are described by MediciNova as consisting of eosinophil migration inhibition, leukotriene antagonism, and phosphodiesterase IV inhibition. Other mechanisms described for Tioxaprofen include the inhibition of phosphodiesterases III, 5-lipoxygenase, phospholipase C as well as thromboxane A2. Tioxaprofen in doses of 1 and 5 mg/kg inhibits bronchoconstriction induced by inhalation of antigen and propranolol in a dose-dependent manner. Tioxaprofen was in phase III clinical trial for the treatment of asthma. However, this development was discontinued. It is under investigation for the treatment of idiopathic pulmonary fibrosis and Non-alcoholic steatohepatitis.

Topilutamide is a non-steroidal anti-androgen. Topilutamide downregulated androgen receptor expression by 40% at 3 uM and up to 95% at 10 uM in LNCaP Cells After 48-h drug incubation. While highly hydrophobic and hydrolytically degradable, it is systemically nonresorbable. In animals, fluridil demonstrated high local and general tolerance. After 3 months of topical application of topilutamide, the average anagen percentage did not change in placebo subjects but increased in topilutamide subjects (male with androgenetic alopecia) from 76% to 85%, and at 9 months to 87%. In former placebo subjects, topilutamide increased the anagen percentage after 6 months from 76% to 85%. Sexual functions, libido, hematology, and blood chemistry values were normal.