Idalopirdine (Lu AE58054) is a Serotonin 6 receptor (5-HT6) antagonist. Idalopirdine exrets good oral bioavailability and robust efficacy in a rat model of cognitive impairment in schizophrenia. In rats idalopirdine potentiates the effects of acetylcholinesterase inhibitor donepezil on two pharmacodynamic biomarkers associated with cognition, i.e. neuronal oscillations and extracellular ACh levels in the hippocampus. Such potentiation could contribute to the procognitive effects of idalopirdine observed in donepezil-treated Alzheimer's disease patients. The compound is being developed by Lundbeck as an adjunctive therapy with acetylcholinesterase inhibitor donepezil, and is in phase III development for the treatment of Alzheimer's disease in multiple countries worldwide. A phase II trial for the treatment of cognitive impairment associated with schizophrenia was conducted; however no recent reports of development for idalopirdine have been identified.

FK-960 [N-(4-acetyl-1-piperazinyl)-p-fluorobenzamide monohydrate], a novel putative anti-dementia drug of piperazine derivative, ameliorates memory deficits in a variety of animal models of dementia in rats and monkeys, and also augments long-term potentiation (LTP) in the mossy fiber-CA3 pathway in guinea-pig hippocampal slices. FK-960 acts as Serotonin modulator. FK-960 had been in phase II clinical trials by Fujisawa Pharmaceutical (now Astellas) for the treatment of Alzheimer's disease (AD). However this study was suspended. In 2003 Phase-II for Alzheimer's disease in USA was discontinued and in Jul 2004 - Phase-II for Cognition disorders in Europe.

JNJ-40418677 is an inhibitor of gamma-secretase. JNJ-40418677 selectively reduced amyloid β 42 secretion in human neuroblastoma cells and rat primary neurones, but it did not inhibit Notch processing or formation of other amyloid precursor protein cleavage products. Oral treatment of non-transgenic mice with JNJ-40418677 resulted in an excellent brain penetration of the compound and a dose- and time-dependent decrease of brain amyloid β 42 levels. Chronic treatment of Tg2576 mice (a mouse model of Alzheimer's disease) with JNJ-40418677 reduced brain amyloid β levels, the area occupied by plaques and plaque number in a dose-dependent manner compared with transgenic vehicle-treated mice.

S-17092, a prolyl endopeptidase inhibitor, is in phase I investigations with Servier in France for its potential in cognition disorders. Prolyl endopeptidase is involved in the metabolic breakdown of a number of neuropeptide neurotransmitters in the brain, and so inhibiting the action of the enzyme increases the activity of these neuropeptides. This produces nootropic effects which make S-17092 a promising and novel treatment for neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease.

77-LH-28-1 Oxalate is a salt of 77-LH-28-1. This drug is a potent, selective, bioavailable and brain-penetrant agonist of muscarinic acetylcholine receptor subtype 1. 77-LH-28-1 can increase network oscillations relevant to cognitive processing that would support the potential use of this mechanism in the treatment of cognitive impairment. 77-LH-28-1 exhibited U-shaped dose-effect functions in attenuating cocaine discrimination. 77-LH-28-1, can significantly enhance donepezil-induced gamma oscillations. These data support the notion that it should be possible to find a more efficacious AChE inhibitor or an adjunctive approach, to provide a better therapeutic intervention in Alzheimer's disease.

BMS-299897 is an orally bioavailable, sulfonamide γ-secretase inhibitor with an IC50 of 7 nM for Aβ production inhibition in HEK293 cells stably overexpressing amyloid precursor protein (APP). BMS-299897 has the potential for treatment of Alzheimer's disease.

Tubastatin A is a potent and selective HDAC6 inhibitor with IC50 of 15 nM in a cell-free assay. Tubastatin A is a very selective HDAC6 inhibitor with 100 to over 1000-fold selectivity for HDAC6 over other HDAC classes. Tubastatin A increases the total numbers of mitochondria and restores the number of moving mitochondria in DRG neurons. It reverses the axonal loss in peripheral neurons in the mouse model of Charcot-Marie-Tooth disease. Tubastatin A inhibits the deacetylation of α-tubulin in murine myoblasts.

AZ-1080 (AZD-1080) is an inhibitor of GSK-beta which was developed by AstraZeneca and initially tested in patients with Alzheimer’s disease (phase I). The drug was discontinued for the aforementioned condition, but now it is being investigated as a potential therapy for ovarina cancer and emdometrial carcinoma (basic research).

ASP-2535 is a glycine transporter-1 (GlyT1) inhibitor which was developed by Astellas Pharma for the treatment of Schizophrenia and Alzheimer's disease. Although ASP-2535 was shown to improve cognitive impairment in animal models, it is no longer in the company pipeline.

Senegenin (Tenuigenin) is a natural product from Polygala tenuifolia used in Chinese medicine to improve memory and intelligence. Senegenin attenuated hepatic ischemia-reperfusion induced cognitive dysfunction via increasing NR2B expression in rat hippocampus. Senegenin displayed antiapoptotic and antioxidative activity in hippocampal neurons due to scavenging of intracellular reactive oxygen species, regulating Bcl-2 family and suppressing caspase-3 activity. In vitro studies have indicated that senegenin treatment suppresses secretion of amyloid β protein and attenuate its cytotoxicity. Anti-inflammatory effect of senegenin is expressed via inhibition of NF-κB activation and was investigated in preclinical models of pneumonia, osteoarthritis, acute liver injury and other diseases.