Acolbifene, the active metabolite of EM-800, was identified as a pure antagonist that acts on both activation domains of the ERs. It is in Phase III clinical trials for the prevention of breast cancer and vasomotor symptoms (Hot flush) in postmenopausal women. Most commonly reported adverse events included irregular menses, leg/muscle cramps, diarrhea, and hot flashes. No serious adverse events were reported.

Nemazoline (A-57219) is a nasal decongestant. It has alpha 1-agonist/alpha 2-antagonist activity and was more effective and long-acting than oxymetazoline on canine nasal mucosa, in-vitro and in-vivo. Upon intranasal administration to dogs, the compound was devoid of systemic effects up to a concentration 1000 times that needed for local decongestant effect (1.65 micrograms, atomized from a 1 microgram mL-1 solution) suggesting limited mucosal absorption. After nasal administration to rats for 15 days at a concentration 1000 times greater than that required for nasal decongestion, no mucosal tissue toxicity or systemic effects were seen.

Lubazodone (YM 992) or (S)-2-[[(7-fluoro-4-indanyl)oxy]methyl]morpholine monohydrochloride, exhibited the biochemical profile of a selective serotonin (5-HT) reuptake inhibitor (SSRI) with 5-HT2A receptor antagonistic activity. It has been studied in the treatment of depression.

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.

Alvameline is a partial agonist of the M1 mAChR that also displays M2/M3 antagonist effects. It readily crosses the blood-brain barrier. It has an effect profile that makes it of interest to test its ability to counteract bladder overactivity in humans. Behaviorally, alvameline has been shown to significantly improve Morris water maze (MWM) performance in both young and ageimpaired rats. It failed to improve cognition in patients with mild to moderate Alzheimer's disease.

Enrasentan is an orally active mixed endothelin A/B receptor antagonist with a 100-fold greater affinity for the endothelin A receptor. In an animal model of hypertension and cardiac hypertrophy the drug has reduced blood pressure, prevented cardiac hypertrophy and preserved myocardial function. In rats with hyperinsulinemia and hypertension enrasentan normalized blood pressure and prevented cardiac and renal damage. In rats with stroke the drug reduced the ischemic area in the brain. Enrasentan had been in phase II clinical trial for the treatment of heart failure but the results suggested that enrasentan does not appear to have favorable effects on ventricular remodeling.

Eplivanserin (SR 46349) is an antagonist of serotonin 2A receptor. Eplivanserin was previously in development by Sanofi-aventis in an effort to educate the public regarding this new mechanism of action for sleep aids. Eplivanserin was reviewed by the FDA as a potential treatment for patients with chronic insomnia, but the FDA requested additional information regarding benefit-risk and development of the drug has been discontinued.

Mazapertine (RWJ-37796) is an arylpiperazine antipsychotic with high affinity to dopamine D2 and D3, serotonin 5-HT1A and alpha 1A-adrenergic receptors. It was being studied in the treatment of schizophrenia.

Ifetroban was developed as a thromboxane A2/prostaglandin H2 receptor antagonist by Bristol-Myers Squibb for cardiovascular indications. In spite of the positive preclinical results where the drug has shown the cardioprotective and antithrombotic activities and was effective. The development of this drug for coronary thrombosis, peripheral vascular disorders, and thrombosis was discontinued. Bristol-Myers Squibb donated the entire program to Vanderbilt University, which further identified ifetroban’s potential in treating patients for several niche indications. Cumberland acquired the ifetroban program from Vanderbilt through its majority-owned subsidiary, Cumberland Emerging Technologies taking responsibility for development and commercialization of the product. Ifetroban oral capsule is being developed by Cumberland for the treatment of systemic sclerosis (SSc) also called scleroderma. With pulmonary disease emerging as the major cause of death in SSc patients, preclinical work indicates that ifetroban is capable of preventing cardiac fibrosis in a model of pulmonary arterial hypertension. In addition, this drug successfully completed phase II clinical trials for the treatment of hepatorenal syndrome (HRS) in hospitalized adult patients, where were determined the safety and pharmacokinetics of 3 days of intravenous ifetroban. In addition, the recruitment is anticipated for Phase 2 study of daily, oral anti-fibrotic therapy to prevent heart muscle disease and improve heart muscle function in ambulatory and non-ambulatory Duchenne patients. In December 2018, Vanderbilt-Ingram Cancer Center and Cumberland Pharmaceuticals initiated a phase II trial to assess the safety and feasibility of ifetroban in treating patients with malignant solid tumors that are at high risk of coming back after treatment and spreading throughout the body.

Tesmilifene is a small-molecule antineoplastic drug and chemopotentiator that was under development by YM BioSciences for the treatment of breast cancer. Tesmilifene was developed as a selective ligand of the antiestrogen binding sites without estrogen receptor affinity. Tesmilifene potentiates the cytotoxicity of a variety of chemotherapy drugs in vitro and in vivo. Tesmilifene in combination with doxorubicin provides an unexpected and very large survival advantage over doxorubicin alone in a randomized trial in phase III clinical trial in advanced breast cancer. Unfortunately, Tesmilifene application associated with high rate disease and treatment-related adverse events and poor quality of life. Based on these results further development of Tesmilifene was discontinued