Eliprodil, also known as SL 82-0715, is a non-competitive NMDA glutamate receptor antagonist, which targets the polyamine modulatory site and is selective for NR2B subunit-containing receptors. Eliprodil was in phase III clinical trial for the treatment of stroke or traumatic brain injury. However, these investigations were failed. One reason suggested for failure was that eliprodil had blocked the synaptic transmission mediated by NMDA receptors, hindering neuronal survival. In addition, eliprodil has been studied in phase II clinical trials for the treatment of Parkinson's disease.

Dimiracetam is a nootropic drug of the racetam family. Dimiracetam inhibited the NMDA-induced increase of [3H]D-Asp release from hippocampal synaptosomes. The increased potency and longer duration of action of dimiracetam, together with the potential cognition enhancing property makes it a very promising and safe for the treatment of neuropathic pain conditions for which there are very limited therapeutic options. Dimiracetam is in Phase II clinical trials for the treatment of HIV-associated pain and in phase I clinical trials for the treatment of osteoarthritis pain.

Early explorations of spider and scorpion venoms provided clues for the discovery of new classes of compounds, including delucemine, that act as neuroprotectants in animal models of stroke. This compound targets open NMDA receptor-operated calcium channels and blocks the channel. By blocking these channels, which open in response to the neurotransmitter glutamate, delucemine prevents excessive calcium influx during ischemia. This stabilizes cell chemistry and minimizes cell death. Delucemine attenuated short-term cognitive deficits and histopathological changes associated with traumatic brain injury. Delucemine improved measures of brain tissue edema and ion homeostasis.

Totrombopag is an orally bioavailable, nonpeptide, small-molecule thrombopoietin receptor agonist. It induces proliferation and differentiation of megakaryocytes and progenitor cells, ultimately increasing the production of platelets. Totrombopag has been investigated in healthy volunteers in a phase 1, single-blind, randomized fashion to cause a dosedependent increase in platelet count with demonstrated safety. There were no serious adverse events, no significant changes in laboratory or cardiovascular safety parameters and there was no observed relationship between the incidence or severity of adverse events and dose. Most adverse events were mild in intensity and self-limiting. Totrombopag was developed for the treatment of immune thrombocytopenic purpura.

Verubecestat (MK 8931) is a potentially first-in-class, potent β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor being developed by Merck. Verubecestat (MK-8931) is a selective, structurally unique BACE1 inhibitor that reduced plasma, cerebrospinal fluid (CSF), and brain concentrations of Aβ40, Aβ42, and sAPPβ (a direct product of BACE1 enzymatic activity) after acute and chronic administration to rats and monkeys. Verubecestat was under investigation for the treatment of Alzheimer's disease, prodromal Alzheimer's disease, and amnestic mild cognitive impairment. In November 2013, Merck began the APECS trial in 1,500 participants with prodromal AD, aka mild cognitive impairment due to AD (aMCI). These patients have measurable cognitive deficits and a positive PET scan with the newly FDA-approved amyloid tracer flutemetamol, but are not functionally impaired. APECS compared 12 and 40 mg once-daily doses to placebo; treatment was to last for two years. APECS usef change from baseline on the Clinical Dementia Rating Sum of Boxes (CDR-SB), a continuous measure, as its primary outcome. Secondary outcomes evaluated a range of newer measures, including a cognitive composite, CSF tau, brain imaging of hippocampal volume and amyloid load, and others. This trial was being conducted in more than 90 locations worldwide; it completed enrollment in November 2016 and was expected to complete data collection for its primary outcome in 2019. In February 2018, APECS was discontinued and Merck no longer listed verubecestat in its research pipeline. APECS participants on 40 mg verubecestat scored worse than the placebo group on the CDR-SB and ADAS-Cog13 starting at 13 weeks. The effect was small and did not progress over time. The 12 mg treatment group also performed slightly worse than controls, with the difference reaching significance at scattered time points.

Volixibat (SHP626; formerly LUM002) is a potent inhibitor of the apical sodium-dependent bile acid transporter (ASBT) that was developed for the treatment of nonalcoholic steatohepatitis. Volixibat participated in phase II clinical trial to investigate its safety, effectiveness in adults with nonalcoholic steatohepatitis. However, this study was discontinued, without any further explanation for the possible causes. In addition, volixibat was studied in a clinical trial in healthy adults and in patients with type 2 diabetes mellitus, where was shown that the drug was generally well tolerated.

4‐Chlorokynurenine (AV-101) is a neuropharmaceutical drug candidate in development for the treatment of major depressive disorder. Pharmacology studies conducted in rodent models have demonstrated AV-101’s antihyperalgesic activity in models of facilitated pain processing was seen at serum concentrations ranging from 150–300 M. In addition, AV-101 has been shown to be neuroprotective activity against an intrahippocampal injection of quinolinic acid, reductions in seizures, and antidepressive activity. An oral prodrug, AV-101, which, in the brain, is converted into one of the most potent and selective GlyB site antagonists of the NMDAR, has been demonstrated to be active in animal models of neuropathic pain. The two Phase 1 studies were designed to assess the safety and pharmacokinetics of AV-101, over a wide dose range, after daily dosing for 14-days. AV-101 has excellent safety and PK characteristics providing support for advancing AV-101 into Phase 2 studies in neuropathic pain.